Dr. Maya Koronyo-Hamaoui, PhD - Cedars-Sinai Medical Center - Associate Professor of Neurosurgery & Biomedical Sciences

Dr. Maya Koronyo-Hamaoui

PhD

Cedars-Sinai Medical Center

Associate Professor of Neurosurgery & Biomedical Sciences

Los Angeles, California | United States

Main Specialties: Neurological Surgery

Additional Specialties: Neuroimmunology, Alzheimer's disease

ORCID logohttps://orcid.org/0000-0003-2864-8442

Dr. Maya Koronyo-Hamaoui, PhD - Cedars-Sinai Medical Center - Associate Professor of Neurosurgery & Biomedical Sciences

Dr. Maya Koronyo-Hamaoui

PhD

Introduction

A major focus of Koronyo-Hamaoui’s research is investigating the role of innate immune cells – especially peripheral monocytes and macrophages – in CNS repair and regeneration, and the development of immunomodulation-based treatments for Alzheimer’s disease (AD). In addition, she is exploring the pathological changes in the retina specific to AD for the prospect of early screening and tracking response to therapy. She is a pioneer in identifying the pathological hallmark of AD, A? plaques, in the retina of AD patients, including early-stage cases. Her team further developed a breakthrough noninvasive approach for detection of retinal A? deposits in living patients using high-resolution optical retinal imaging. Currently, her lab is probing neuroinflammation, tauopathy and vascular biomarkers in the retina of MCI and AD patients while establishing their relationship with disease in the brain.

Primary Affiliation: Cedars-Sinai Medical Center - Los Angeles, California , United States

Specialties:

Additional Specialties:

Education

Nov 2006
The Weizmann Institute of Science, Rehovot, Israel
Postdoc
Neuroimmunology, Alzheimer's disease
Feb 2005
Sackler School of Medicine, Tel-Aviv University, Israel
Ph.D.
Human molecular genetics, psychiatric genetics, Eating disorders, Schizophrenia, OCD
Aug 1998
Sackler School of Medicine, Tel-Aviv University, Israel
M.Sc.
summa cum laude; Human molecular genetics, neuromuscular diseases (CAG repeats)
Aug 1995
Life Sciences Faculty, Tel-Aviv University, Israel
B.Sc.
cum laude; Biology

Experience

Apr 2018
NIA R01 AG055865
PI
Alzheimer’s Disease Hallmark Pathology and Associated Inflammation in the Retina
Sep 2017
NIA R01 AG056478
PI
Retinal Imaging of Alzheimer’s Disease Pathology
Dec 2015
SBMT Board of Directors
Board member
Society for Brain Mapping
Jul 2013
NIA R41 AG044897
PI
A non-invasive optical imaging methodology to detect retinal amyloid-? in Alzheimer’s disease patients
Jul 2013
The BrightFocus Foundation (AHAF) - Alzheimer’s Disease Research Award
PI
Therapeutic roles of ACE-overexpressing monocytes in AD
Apr 2013
Pioneer in Medicine Award, The Brain Mapping Foundation
Recipient
Retinal Imaging in AD
Jul 2012
Primary Research Award from the Coins for Alzheimer’s Research Trust (CART) Fund
PI
Targeted macrophage ACE-overexpression as a therapy for Alzheimer’s disease
Dec 2011
Editorial Board
Editor
Public Library of Science (PLoS and PLoSONE) , Frontiers in Immunology

Publications

41Publications

1015Reads

135Profile Views

77PubMed Central Citations

Identification of early pericyte loss and vascular amyloidosis in Alzheimer's disease retina.

Acta Neuropathol 2020 05 10;139(5):813-836. Epub 2020 Feb 10.

Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd., Los Angeles, CA, 90048, USA.

Pericyte loss and deficient vascular platelet-derived growth factor receptor-? (PDGFR?) signaling are prominent features of the blood-brain barrier breakdown described in Alzheimer's disease (AD) that can predict cognitive decline yet have never been studied in the retina. Recent reports using noninvasive retinal amyloid imaging, optical coherence tomography angiography, and histological examinations support the existence of vascular-structural abnormalities and vascular amyloid ?-protein (A?) deposits in retinas of AD patients. However, the cellular and molecular mechanisms of such retinal vascular pathology were not previously explored. Here, by modifying a method of enzymatically clearing non-vascular retinal tissue and fluorescent immunolabeling of the isolated blood vessel network, we identified substantial pericyte loss together with significant A? deposition in retinal microvasculature and pericytes in AD. Evaluation of postmortem retinas from a cohort of 56 human donors revealed an early and progressive decrease in vascular PDGFR? in mild cognitive impairment (MCI) and AD compared to cognitively normal controls. Retinal PDGFR? loss significantly associated with increased retinal vascular A? and A? burden. Decreased vascular LRP-1 and early apoptosis of pericytes in AD retina were also detected. Mapping of PDGFR? and A? levels in pre-defined retinal subregions indicated that certain geometrical and cellular layers are more susceptible to AD pathology. Further, correlations were identified between retinal vascular abnormalities and cerebral A? burden, cerebral amyloid angiopathy (CAA), and clinical status. Overall, the identification of pericyte and PDGFR? loss accompanying increased vascular amyloidosis in Alzheimer's retina implies compromised blood-retinal barrier integrity and provides new targets for AD diagnosis and therapy.

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http://dx.doi.org/10.1007/s00401-020-02134-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181564PMC
May 2020
18.174 Impact Factor

Future avenues for Alzheimer's disease detection and therapy: Liquid biopsy, intracellular signaling modulation, systems pharmacology drug discovery.

Neuropharmacology 2020 May 11:108081. Epub 2020 May 11.

Sorbonne University, GRC N° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de L'hôpital, F-75013, Paris, France; Brain & Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de L'hôpital, F-75013, Paris, France; Institute of Memory and Alzheimer's Disease (IM2A), Department of Neurology, Pitié-Salpêtrière Hospital, AP-HP, Boulevard de L'hôpital, F-75013, Paris, France.

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http://dx.doi.org/10.1016/j.neuropharm.2020.108081DOI Listing
May 2020
5.106 Impact Factor

The path to biomarker-based diagnostic criteria for the spectrum of neurodegenerative diseases.

Expert Rev Mol Diagn 2020 Apr 27;20(4):421-441. Epub 2020 Feb 27.

Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France.

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http://dx.doi.org/10.1080/14737159.2020.1731306DOI Listing
April 2020
3.516 Impact Factor

Retinal vessel changes in cerebrovascular disease.

Curr Opin Neurol 2020 Feb;33(1):87-92

Department of Neurosurgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.

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http://dx.doi.org/10.1097/WCO.0000000000000779DOI Listing
February 2020
5.307 Impact Factor

Overexpression of ACE in Myeloid Cells Increases Immune Effectiveness and Leads to a New Way of Considering Inflammation in Acute and Chronic Diseases.

Curr Hypertens Rep 2020 Jan 8;22(1). Epub 2020 Jan 8.

Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.

Purpose Of Review: To review recent studies exploring how myeloid cell overexpression of angiotensin-converting enzyme (ACE) affects the immune response and to formulate an approach for considering the effectiveness of inflammation in cardiovascular disease RECENT FINDINGS: While it is widely appreciated that the renin-angiotensin system affects aspects of inflammation through the action of angiotensin II, new studies reveal a previously unknown role of ACE in myeloid cell biology. This was apparent from analysis of two mouse lines genetically modified to overexpress ACE in monocytes/macrophages or neutrophils. Cells overexpressing ACE demonstrated an increased immune response. For example, mice with increased macrophage ACE expression have increased resistance to melanoma, methicillin-resistant Staphylococcus aureus, a mouse model of Alzheimer's disease, and ApoE-knockout-induced atherosclerosis. These data indicate the profound effect of increasing myeloid cell function. Further, they suggest that an appropriate way to evaluate inflammation in both acute and chronic diseases is to ask whether the inflammatory infiltrate is sufficient to eliminate the immune challenge. The expression of ACE by myeloid cells induces a heightened immune response by these cells. The overexpression of ACE is associated with immune function beyond that possible by wild type (WT) myeloid cells. A heightened immune response effectively resolves disease in a variety of acute and chronic models of disease including models of Alzheimer's disease and atherosclerosis.

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http://dx.doi.org/10.1007/s11906-019-1008-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213017PMC
January 2020
3.606 Impact Factor

Plasma tau correlates with basal forebrain atrophy rates in people at risk for Alzheimer disease.

Neurology 2020 01 4;94(1):e30-e41. Epub 2019 Dec 4.

From Alzheimer Precision Medicine (APM) (E.C., S.L., A.V., B.D., H.H.), AP-HP, Pitié-Salpêtrière Hospital, Sorbonne University; Brain & Spine Institute (ICM) (E.C., S.L., M.H., A.V., M.C.P., B.D.), INSERM U 1127, CNRS UMR 7225; Institute of Memory and Alzheimer's Disease (IM2A) (E.C., S.L., M.H., A.V., B.D.), Department of Neurology, Pitié-Salpêtrière Hospital, AP-HP; Qynapse (E.C.); Centre of Excellence of Neurodegenerative Disease (CoEN) (M.H.), ICM, CIC Neurosciences, APHP Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, France; German Center for Neurodegenerative Diseases (DZNE)-Rostock/Greifswald (M.J.G., S.T.); Department of Psychosomatic Medicine (M.J.G., S.T.), University of Rostock, Germany; Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry (H.Z.), the Sahlgrenska Academy at the University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease (H.Z., K.B.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (H.Z., K.B.), London, UK; Laboratoire d'Imagerie Biomédicale (M.-O.H.), Sorbonne Université, CNRS, INSERM; Centre pour l'Acquisition et le Traitement des Images (cati-neuroimaging.com) (M.-O.H.); and Département de Médecine Nucléaire (M.-O.H.), AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.

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http://dx.doi.org/10.1212/WNL.0000000000008696DOI Listing
January 2020
8.286 Impact Factor

Peripherally derived angiotensin converting enzyme-enhanced macrophages alleviate Alzheimer-related disease.

Brain 2020 01;143(1):336-358

Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Targeted overexpression of angiotensin-converting enzyme (ACE), an amyloid-? protein degrading enzyme, to brain resident microglia and peripheral myelomonocytes (ACE10 model) substantially diminished Alzheimer's-like disease in double-transgenic APPSWE/PS1?E9 (AD+) mice. In this study, we explored the impact of selective and transient angiotensin-converting enzyme overexpression on macrophage behaviour and the relative contribution of bone marrow-derived ACE10 macrophages, but not microglia, in attenuating disease progression. To this end, two in vivo approaches were applied in AD+ mice: (i) ACE10/GFP+ bone marrow transplantation with head shielding; and (ii) adoptive transfer of CD115+-ACE10/GFP+ monocytes to the peripheral blood. Extensive in vitro studies were further undertaken to establish the unique ACE10-macrophage phenotype(s) in response to amyloid-?1-42 fibrils and oligomers. The combined in vivo approaches showed that increased cerebral infiltration of ACE10 as compared to wild-type monocytes (?3-fold increase; P < 0.05) led to reductions in cerebral soluble amyloid-?1-42, vascular and parenchymal amyloid-? deposits, and astrocytosis (31%, 47-80%, and 33%, respectively; P < 0.05-0.0001). ACE10 macrophages surrounded brain and retinal amyloid-? plaques and expressed 3.2-fold higher insulin-like growth factor-1 (P < 0.01) and ?60% lower tumour necrosis factor-? (P < 0.05). Importantly, blood enrichment with CD115+-ACE10 monocytes in symptomatic AD+ mice resulted in pronounced synaptic and cognitive preservation (P < 0.05-0.001). In vitro analysis of macrophage response to well-defined amyloid-?1-42 conformers (fibrils, prion rod-like structures, and stabilized soluble oligomers) revealed extensive resistance to amyloid-?1-42 species by ACE10 macrophages. They exhibited 2-5-fold increased surface binding to amyloid-? conformers as well as substantially more effective amyloid-?1-42 uptake, at least 8-fold higher than those of wild-type macrophages (P < 0.0001), which were associated with enhanced expression of surface scavenger receptors (i.e. CD36, scavenger receptor class A member 1, triggering receptor expressed on myeloid cells 2, CD163; P < 0.05-0.0001), endosomal processing (P < 0.05-0.0001), and ?80% increased extracellular degradation of amyloid-?1-42 (P < 0.001). Beneficial ACE10 phenotype was reversed by the angiotensin-converting enzyme inhibitor (lisinopril) and thus was dependent on angiotensin-converting enzyme catalytic activity. Further, ACE10 macrophages presented distinct anti-inflammatory (low inducible nitric oxide synthase and lower tumour necrosis factor-?), pro-healing immune profiles (high insulin-like growth factor-1, elongated cell morphology), even following exposure to Alzheimer's-related amyloid-?1-42 oligomers. Overall, we provide the first evidence for therapeutic roles of angiotensin-converting enzyme-overexpressing macrophages in preserving synapses and cognition, attenuating neuropathology and neuroinflammation, and enhancing resistance to defined pathognomonic amyloid-? forms.

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http://dx.doi.org/10.1093/brain/awz364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935752PMC
January 2020
48 Reads
11.814 Impact Factor

Advances In Retinal Imaging: Retinal Amyloid Imaging. In: Grzybowski A., Barboni P. (eds) OCT and Imaging in Central Nervous System Diseases.

https://doi.org/10.1007/978-3-030-26269-3_6

Springer, Cham

Growing evidence indicates that the brain is not the only CNS tissue affected by Alzheimer’s disease (AD) pathology—the retina is also afflicted with the pathological hallmarks Aβ and tau, as well as associated inflammation, neurodegeneration, astrogliosis, and vascular abnormalities. Current molecular imaging modalities for AD-specific diagnosis and disease monitoring are limited by high cost, invasiveness, inaccessibility, and safety concerns. Therefore, a noninvasive, easy-to-use, and inexpensive imaging technique to definitively diagnose AD pathological changes in living patients and to monitor response to therapy is desperately needed. One such technique, a noninvasive retinal amyloid imaging, was developed and recently translated in a proof-of-concept clinical study. The histological and biochemical evidence of AD biomarkers in the retina, their correlation with disease in the brain, together with emerging new retinal imaging techniques provide new hope for advancing early diagnosis and therapy for this devastating disease.

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January 2020
3 Reads

Brain Aβ load association and sexual dimorphism of plasma BACE1 concentrations in cognitively normal individuals at risk for AD.

Alzheimers Dement 2019 10;15(10):1274-1285

Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France; Eisai Inc., Neurology Business Group, Woodcliff Lake, NJ, USA.

Introduction: Successful development of effective ?-site amyloid precursor protein cleaving enzyme 1 (BACE1)-targeted therapies for early stages of Alzheimer's disease requires biomarker-guided intervention strategies.

Methods: We investigated whether key biological factors such as sex, apolipoprotein E (APOE ?4) allele, and age affect longitudinal plasma BACE1 concentrations in a large monocenter cohort of individuals at risk for Alzheimer's disease. We explored the relationship between plasma BACE1 concentrations and levels of brain amyloid-? (A?) deposition, using positron emission tomography global standard uptake value ratios.

Results: Baseline and longitudinal mean concentrations of plasma BACE1 were significantly higher in women than men. We also found a positive significant impact of plasma BACE1 on baseline A?-positron emission tomography global standard uptake value ratios.

Discussion: Our results suggest a sexual dimorphism in BACE1-related upstream mechanisms of brain A? production and deposition. We argue that plasma BACE1 should be considered in further biomarker validation and qualification studies as well as in BACE1 clinical trials.

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http://dx.doi.org/10.1016/j.jalz.2019.07.001DOI Listing
October 2019
1 Read
14.423 Impact Factor

Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease.

Alzheimers Dement 2019 07 18;15(7):940-950. Epub 2019 May 18.

Sorbonne University, GRC no 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France.

Introduction: The longitudinal trajectories of functional brain dynamics and the impact of genetic risk factors in individuals at risk for Alzheimer's disease are poorly understood.

Methods: In a large-scale monocentric cohort of 224 amyloid stratified individuals at risk for Alzheimer's disease, default mode network (DMN) resting state functional connectivity (FC) was investigated between two serial time points across 2 years.

Results: Widespread DMN FC changes were shown in frontal and posterior areas, as well as in the right hippocampus. There were no cross-sectional differences, however, apolipoprotein E ?4 (APOE ?4) carriers demonstrated slower increase in FC in frontal lobes. There was no impact of individual brain amyloid load status.

Discussion: For the first time, we demonstrated that the pleiotropic biological effect of the APOE ?4 allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkers may become useful surrogate outcomes for the development of preclinical targeted therapeutic interventions.

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http://dx.doi.org/10.1016/j.jalz.2019.03.006DOI Listing
July 2019
7 Reads
14.423 Impact Factor

Plasma amyloid β 40/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer's disease.

Alzheimers Dement 2019 06 18;15(6):764-775. Epub 2019 May 18.

Sorbonne University, GRC no 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France.

Introduction: Blood-based biomarkers of pathophysiological brain amyloid ? (A?) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management.

Methods: We investigated whether plasma concentrations of the A?/A? ratio, assessed using the single-molecule array (Simoa) immunoassay, may predict brain A? positron emission tomography status in a large-scale longitudinal monocentric cohort (N = 276) of older individuals with subjective memory complaints. We performed a hypothesis-driven investigation followed by a no-a-priori hypothesis study using machine learning.

Results: The receiver operating characteristic curve and machine learning showed a balanced accuracy of 76.5% and 81%, respectively, for the plasma A?/A? ratio. The accuracy is not affected by the apolipoprotein E (APOE) ?4 allele, sex, or age.

Discussion: Our results encourage an independent validation cohort study to confirm the indication that the plasma A?/A? ratio, assessed via Simoa, may improve future standard of care and clinical trial design.

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http://dx.doi.org/10.1016/j.jalz.2019.03.009DOI Listing
June 2019
14 Reads
14.423 Impact Factor

Acute neuropathological consequences of short-term mechanical ventilation in wild-type and Alzheimer's disease mice.

Crit Care 2019 02 22;23(1):63. Epub 2019 Feb 22.

Department of Neurosurgery, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd., AHSP Building, Suite A6600, A8103, Los Angeles, CA, 90048, USA.

Background: Mechanical ventilation is strongly associated with cognitive decline after critical illness. This finding is particularly evident among older individuals who have pre-existing cognitive impairment, most commonly characterized by varying degrees of cerebral amyloid-? accumulation, neuroinflammation, and blood-brain barrier dysfunction. We sought to test the hypothesis that short-term mechanical ventilation contributes to the neuropathology of cognitive impairment by (i) increasing cerebral amyloid-? accumulation in mice with pre-existing Alzheimer's disease pathology, (ii) increasing neurologic and systemic inflammation in wild-type mice and mice with pre-existing Alzheimer's disease pathology, and (iii) increasing hippocampal blood-brain barrier permeability in wild-type mice and mice with pre-existing Alzheimer's disease pathology.

Methods: We subjected double transgenic Alzheimer's disease (APP/PSEN1) and wild-type mice to mechanical ventilation for 4?h and compared to non-mechanically ventilated Alzheimer's disease model and wild-type mice. Cerebral soluble/insoluble amyloid-?/amyloid-? and neurological and systemic markers of inflammation were quantified. Hippocampal blood-brain barrier permeability was quantified using a novel methodology that enabled assessment of small and large molecule permeability across the blood-brain barrier.

Results: Mechanical ventilation resulted in (i) a significant increase in cerebral soluble amyloid-? (p?=?0.007) and (ii) significant increases in neuroinflammatory cytokines in both wild-type and Alzheimer's disease mice which, in most cases, were not reflected in the plasma. There were (i) direct correlations between polymorphonuclear cells in the bronchoalveolar fluid and cerebral soluble amyloid-? (p?=?0.0033), and several Alzheimer's disease-relevant neuroinflammatory biomarkers including cerebral TNF-? and IL-6; (iii) significant decreases in blood-brain barrier permeability in mechanically ventilated Alzheimer's disease mice and a trend towards increased blood-brain barrier permeability in mechanically ventilated wild-type mice.

Conclusions: These results provide the first evidence that short-term mechanical ventilation independently promotes the neuropathology of Alzheimer's disease in subjects with and without pre-existing cerebral Alzheimer's disease pathology. Future studies are needed to further clarify the specific mechanisms by which this occurs and to develop neuroprotective mechanical ventilation strategies that mitigate the risk of cognitive decline after critical illness.

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http://dx.doi.org/10.1186/s13054-019-2356-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387486PMC
February 2019
6 Reads
6.959 Impact Factor

Association of cerebrospinal fluid α-synuclein with total and phospho-tau protein concentrations and brain amyloid load in cognitively normal subjective memory complainers stratified by Alzheimer's disease biomarkers.

Alzheimers Dement 2018 12 26;14(12):1623-1631. Epub 2018 Jul 26.

AXA Research Fund & Sorbonne University Chair, Paris, France; Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France; Brain & Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l'hôpital, Paris, France; Institute of Memory and Alzheimer's Disease (IM2A), Department of Neurology, Pitié-Salpêtrière Hospital, AP-HP, Boulevard de l'hôpital, Paris, France.

Introduction: Several neurodegenerative brain proteinopathies, including Alzheimer's disease (AD), are associated with cerebral deposition of insoluble aggregates of ?-synuclein. Previous studies reported a trend toward increased cerebrospinal fluid (CSF) ?-synuclein (?-syn) concentrations in AD compared with other neurodegenerative diseases and healthy controls.

Methods: The pathophysiological role of CSF ?-syn in asymptomatic subjects at risk of AD has not been explored. We performed a large-scale cross-sectional observational monocentric study of preclinical individuals at risk for AD (INSIGHT-preAD).

Results: We found a positive association between CSF ?-syn concentrations and brain ?-amyloid deposition measures as mean cortical standard uptake value ratios. We demonstrate positive correlations between CSF ?-syn and both CSF t-tau and p-tau concentrations.

Discussion: Animal models presented evidence, indicating that ?-syn may synergistically and directly induce fibrillization of both tau and ?-amyloid. Our data indicate an association of CSF ?-syn with AD-related pathophysiological mechanisms, during the preclinical phase of the disease.

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http://dx.doi.org/10.1016/j.jalz.2018.06.3053DOI Listing
December 2018
21 Reads
14.423 Impact Factor

Sex differences in functional and molecular neuroimaging biomarkers of Alzheimer's disease in a monocenter cohort of cognitively normal older adults with subjective memory complaints

Alzheimer's & Dementia

Introduction Observational multimodal neuroimaging studies indicate sex differences in Alzheimer's disease pathophysiological markers. Methods Positron emission tomography brain amyloid load, neurodegeneration (hippocampus and basal forebrain volumes adjusted to total intracranial volume, cortical thickness, and 2-deoxy-2-[fluorine-18]fluoro-D-glucose–positron emission tomography metabolism), and brain resting-state functional connectivity were analyzed in 318 cognitively intact older adults from the INSIGHT-preAD cohort (female n = 201, male n = 117). A linear mixed-effects model was performed to investigate sex effects and sex–apolipoprotein E genotype interaction on each marker as well as sex-amyloid group interaction for nonamyloid markers. Results Men compared with women showed higher anterior cingulate amyloid load (P = .009), glucose hypometabolism in the precuneus (P = .027), posterior cingulate (P < .001) and inferior parietal (P = .043) cortices, and lower resting-state functional connectivity in the default mode network (P = .024). No brain volumetric markers showed differences between men and women. Sex–apolipoprotein E genotype and sex-amyloid status interactions were not significant. Discussion Our findings suggest that cognitively intact older men compared with women have higher resilience to pathophysiological processes of Alzheimer's disease.

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July 2018

Impact Factor 14.423

6 Reads

A novel role for osteopontin in macrophage-mediated amyloid-β clearance in Alzheimer's models.

Brain Behav Immun 2018 Jan 30;67:163-180. Epub 2017 Aug 30.

Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd., Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Division of Applied Cell Biology and Physiology, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd., Los Angeles, CA 90048, USA. Electronic address:

Osteopontin (OPN), a matricellular immunomodulatory cytokine highly expressed by myelomonocytic cells, is known to regulate immune cell migration, communication, and response to brain injury. Enhanced cerebral recruitment of monocytes achieved through glatiramer acetate (GA) immunization or peripheral blood enrichment with bone marrow (BM)-derived CD115 monocytes (Mo) curbs amyloid ?-protein (A?) neuropathology and preserves cognitive function in murine models of Alzheimer's disease (ADtg mice). To elucidate the beneficial mechanisms of these immunomodulatory approaches in AD, we focused on the potential role of OPN in macrophage-mediated A? clearance. Here, we found extensive OPN upregulation along with reduction of vascular and parenchymal A? burden in cortices and hippocampi of GA-immunized ADtg mice. Treatment combining GA with blood-grafted Mo further increased OPN levels surrounding residual A? plaques. In brains from AD patients and ADtg mice, OPN was also elevated and predominantly expressed by infiltrating GFP- or Iba1-CD45 monocyte-derived macrophages engulfing A? plaques. Following GA immunization, we detected a significant increase in a subpopulation of inflammatory blood monocytes (CD115CD11bLy6C) expressing OPN, and subsequently, an elevated population of OPN-expressing CD11bLy6CCD45 monocyte/macrophages in the brains of these ADtg mice. Correlogram analyses indicate a strong linear correlation between cerebral OPN levels and macrophage infiltration, as well as a tight inverse relation between OPN and A?-plaque burden. In vitro studies corroborate in vivo findings by showing that GA directly upregulates OPN expression in BM-derived macrophages (M?). Further, OPN promotes a phenotypic shift that is highly phagocytic (increased uptake of A? fibrils and surface scavenger receptors) and anti-inflammatory (altered cell morphology, reduced iNOS, and elevated IL-10 and A?-degrading enzyme MMP-9). Inhibition of OPN expression in M?, either by siRNA, knockout (KO), or minocycline, impairs uptake of A? fibrils and hinders GA's neuroprotective effects on macrophage immunological profile. Addition of human recombinant OPN reverses the impaired A? phagocytosis in KO-M?. This study demonstrates that OPN has an essential role in modulating macrophage immunological profile and their ability to resist pathogenic forms of A?.

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http://dx.doi.org/10.1016/j.bbi.2017.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865478PMC
January 2018
60 Reads
6.514 Impact Factor

Optical Coherence Tomography in Alzheimer's Disease and Other Neurodegenerative Diseases.

Front Neurol 2017 19;8:701. Epub 2017 Dec 19.

Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.

Over the past decade, a surge of evidence has documented various pathological processes in the retina of patients suffering from mild cognitive impairment, Alzheimer's disease (AD), Parkinson's disease (PD), and other neurodegenerative diseases. Numerous studies have shown that the retina, a central nervous system tissue formed as a developmental outgrowth of the brain, is profoundly affected by AD. Harboring the earliest detectable disease-specific signs, amyloid ?-protein (A?) plaques, the retina of AD patients undergoes substantial ganglion cell degeneration, thinning of the retinal nerve fiber layer, and loss of axonal projections in the optic nerve, among other abnormalities. More recent investigations described A? plaques in the retina located within sites of neuronal degeneration and occurring in clusters in the mid- and far-periphery of the superior and inferior quadrants, regions that had been previously overlooked. Diverse structural and/or disease-specific changes were also identified in the retina of PD, Huntington's disease, and multiple sclerosis patients. The pathological relationship between the retina and brain prompted the development of imaging tools designed to noninvasively detect and monitor these signs in living patients. One such tool is optical coherence tomography (OCT), uniquely providing high-resolution two-dimensional cross-sectional imaging and three-dimensional volumetric measurements. As such, OCT emerged as a prominent approach for assessing retinal abnormalities , and indeed provided multiple parameters that allowed for the distinction between normal aged individuals and patients with neurodegenerative diseases. Beyond the use of retinal optical fundus imaging, which recently allowed for the detection and quantification of amyloid plaques in living AD patients a wide-field view of the peripheral retina, a major advantage of OCT has been the ability to measure the volumetric changes in specified retinal layers. OCT has proven to be particularly useful in analyzing retinal structural abnormalities consistent with disease pathogenesis. In this review, we provide a summary of OCT findings in the retina of patients with AD and other neurodegenerative diseases. Future studies should explore the combination of imaging early hallmark signs together with structural-functional biomarkers in the accessible retina as a practical means of assessing risk, disease progression, and therapeutic efficacy in these patients.

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http://dx.doi.org/10.3389/fneur.2017.00701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742098PMC
December 2017
25 Reads
3.552 Impact Factor

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer's disease.

JCI Insight 2017 Aug 17;2(16). Epub 2017 Aug 17.

Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Background: Noninvasive detection of Alzheimer's disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid ?-protein (A?) deposits.

Methods: Burden, distribution, cellular layer, and structure of retinal A? plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients.

Results: Histological examination uncovered classical and neuritic-like A? deposits with increased retinal A?42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal A? plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson's r = 0.84-0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal A? assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031).

Conclusion: The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring.

Funding: National Institute on Aging award (AG044897) and The Saban and The Marciano Family Foundations.

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http://dx.doi.org/10.1172/jci.insight.93621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621887PMC
August 2017
123 Reads
6.014 Impact Factor

Clearance of cerebral Aβ in Alzheimer's disease: reassessing the role of microglia and monocytes.

Cell Mol Life Sci 2017 06 14;74(12):2167-2201. Epub 2017 Feb 14.

Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 127 S. San Vicente, AHSP A8115, Los Angeles, CA, 90048, USA.

Deficiency in cerebral amyloid ?-protein (A?) clearance is implicated in the pathogenesis of the common late-onset forms of Alzheimer's disease (AD). Accumulation of misfolded A? in the brain is believed to be a net result of imbalance between its production and removal. This in turn may trigger neuroinflammation, progressive synaptic loss, and ultimately cognitive decline. Clearance of cerebral A? is a complex process mediated by various systems and cell types, including vascular transport across the blood-brain barrier, glymphatic drainage, and engulfment and degradation by resident microglia and infiltrating innate immune cells. Recent studies have highlighted a new, unexpected role for peripheral monocytes and macrophages in restricting cerebral A? fibrils, and possibly soluble oligomers. In AD transgenic (ADtg) mice, monocyte ablation or inhibition of their migration into the brain exacerbated A? pathology, while blood enrichment with monocytes and their increased recruitment to plaque lesion sites greatly diminished A? burden. Profound neuroprotective effects in ADtg mice were further achieved through increased cerebral recruitment of myelomonocytes overexpressing A?-degrading enzymes. This review summarizes the literature on cellular and molecular mechanisms of cerebral A? clearance with an emphasis on the role of peripheral monocytes and macrophages in A? removal.

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http://dx.doi.org/10.1007/s00018-017-2463-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425508PMC
June 2017
23 Reads
7.014 Impact Factor

Drug screening: Don't discount all curcumin trial data.

Authors:
Michal Heger

Nature 2017 03;543(7643):40

University of Amsterdam, the Netherlands.

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http://dx.doi.org/10.1038/543040cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814206PMC
March 2017
5 Reads
44.958 Impact Factor

Ocular indicators of Alzheimer's: exploring disease in the retina.

Acta Neuropathol 2016 12 19;132(6):767-787. Epub 2016 Sep 19.

Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd., Los Angeles, 90048, CA, USA.

Although historically perceived as a disorder confined to the brain, our understanding of Alzheimer's disease (AD) has expanded to include extra-cerebral manifestation, with mounting evidence of abnormalities in the eye. Among ocular tissues, the retina, a developmental outgrowth of the brain, is marked by an array of pathologies in patients suffering from AD, including nerve fiber layer thinning, degeneration of retinal ganglion cells, and changes to vascular parameters. While the hallmark pathological signs of AD, amyloid ?-protein (A?) plaques and neurofibrillary tangles (NFT) comprising hyperphosphorylated tau (pTau) protein, have long been described in the brain, identification of these characteristic biomarkers in the retina has only recently been reported. In particular, A? deposits were discovered in post-mortem retinas of advanced and early stage cases of AD, in stark contrast to non-AD controls. Subsequent studies have reported elevated A? peptides, morphologically diverse A? plaques, and pTau in the retina. In line with the above findings, animal model studies have reported retinal A? deposits and tauopathy, often correlated with local inflammation, retinal ganglion cell degeneration, and functional deficits. This review highlights the converging evidence that AD manifests in the eye, especially in the retina, which can be imaged directly and non-invasively. Visual dysfunction in AD patients, traditionally attributed to well-documented cerebral pathology, can now be reexamined as a direct outcome of retinal abnormalities. As we continue to study the disease in the brain, the emerging field of ocular AD warrants further investigation of how the retina may faithfully reflect the neurological disease. Indeed, detection of retinal AD pathology, particularly the early presenting amyloid biomarkers, using advanced high-resolution imaging techniques may allow large-scale screening and monitoring of at-risk populations.

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http://dx.doi.org/10.1007/s00401-016-1613-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5106496PMC
December 2016
91 Reads
18.174 Impact Factor

Melanopsin retinal ganglion cell loss in Alzheimer disease.

Ann Neurol 2016 Jan 18;79(1):90-109. Epub 2015 Dec 18.

IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.

Objective: Melanopsin retinal ganglion cells (mRGCs) are photoreceptors driving circadian photoentrainment, and circadian dysfunction characterizes Alzheimer disease (AD). We investigated mRGCs in AD, hypothesizing that they contribute to circadian dysfunction.

Methods: We assessed retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) in 21 mild-moderate AD patients, and in a subgroup of 16 we evaluated rest-activity circadian rhythm by actigraphy. We studied postmortem mRGCs by immunohistochemistry in retinas, and axons in optic nerve cross-sections of 14 neuropathologically confirmed AD patients. We coimmunostained for retinal amyloid ? (A?) deposition and melanopsin to locate mRGCs. All AD cohorts were compared with age-matched controls.

Results: We demonstrated an age-related optic neuropathy in AD by OCT, with a significant reduction of RNFL thickness (p = 0.038), more evident in the superior quadrant (p = 0.006). Axonal loss was confirmed in postmortem AD optic nerves. Abnormal circadian function characterized only a subgroup of AD patients. Sleep efficiency was significantly reduced in AD patients (p = 0.001). We also found a significant loss of mRGCs in postmortem AD retinal specimens (p = 0.003) across all ages and abnormal mRGC dendritic morphology and size (p = 0.003). In flat-mounted AD retinas, A? accumulation was remarkably evident inside and around mRGCs.

Interpretation: We show variable degrees of rest-activity circadian dysfunction in AD patients. We also demonstrate age-related loss of optic nerve axons and specifically mRGC loss and pathology in postmortem AD retinal specimens, associated with A? deposition. These results all support the concept that mRGC degeneration is a contributor to circadian rhythm dysfunction in AD.

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http://dx.doi.org/10.1002/ana.24548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737313PMC
January 2016
87 Reads
10.244 Impact Factor

Therapeutic effects of glatiramer acetate and grafted CD115⁺ monocytes in a mouse model of Alzheimer's disease.

Brain 2015 Aug 6;138(Pt 8):2399-422. Epub 2015 Jun 6.

1 Department of Neurosurgery, Maxine-Dunitz Neurosurgical Institute, Cedars-Sinai Medical Centre, Los Angeles, CA 90048, USA 3 Department of Biomedical Sciences, Cedars-Sinai Medical Centre, Los Angeles, CA 90048, USA

Weekly glatiramer acetate immunization of transgenic mice modelling Alzheimer's disease resulted in retained cognition (Morris water maze test), decreased amyloid-? plaque burden, and regulation of local inflammation through a mechanism involving enhanced recruitment of monocytes. Ablation of bone marrow-derived myeloid cells exacerbated plaque pathology, whereas weekly administration of glatiramer acetate enhanced cerebral recruitment of innate immune cells, which dampened the pathology. Here, we assessed the therapeutic potential of grafted CD115(+) monocytes, injected once monthly into the peripheral blood of transgenic APPSWE/PS1?E9 Alzheimer's disease mouse models, with and without weekly immunization of glatiramer acetate, as compared to glatiramer acetate alone. All immune-modulation treatment groups were compared with age-matched phosphate-buffered saline-injected control transgenic and untreated non-transgenic mouse groups. Two independent cohorts of mice were assessed for behavioural performance (6-8 mice/group); treatments started in 10-month-old symptomatic mice and spanned a total of 2 months. For all three treatments, our data suggest a substantial decrease in cognitive deficit as assessed by the Barnes maze test (P < 0.0001-0.001). Improved cognitive function was associated with synaptic preservation and reduction in cerebral amyloid-? protein levels and astrogliosis (P < 0.001 and P < 0.0001), with no apparent additive effects for the combined treatment. The peripherally grafted, green fluorescent protein-labelled and endogenous monocytes, homed to cerebral amyloid plaques and directly engulfed amyloid-?; their recruitment was further enhanced by glatiramer acetate. In glatiramer acetate-immunized mice and, moreover, in the combined treatment group, monocyte recruitment to the brain was coupled with greater elevation of the regulatory cytokine IL10 surrounding amyloid-? plaques. All treated transgenic mice had increased cerebral levels of MMP9 protein (P < 0.05), an enzyme capable of degrading amyloid-?, which was highly expressed by the infiltrating monocytes. In vitro studies using primary cultures of bone marrow monocyte-derived macrophages, demonstrated that glatiramer acetate enhanced the ability of macrophages to phagocytose preformed fibrillar amyloid-?1-42 (P < 0.0001). These glatiramer acetate-treated macrophages exhibited increased expression of the scavenger receptors CD36 and SCARA1 (encoded by MSR1), which can facilitate amyloid-? phagocytosis, and the amyloid-?-degrading enzyme MMP9 (P < 0.0001-0.001). Overall, our studies indicate that increased cerebral infiltration of monocytes, either by enrichment of their levels in the circulation or by weekly immunization with glatiramer acetate, resulted in substantial attenuation of disease progression in murine Alzheimer's models by mechanisms that involved enhanced cellular uptake and enzymatic degradation of toxic amyloid-? as well as regulation of brain inflammation.

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http://dx.doi.org/10.1093/brain/awv150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840949PMC
August 2015
46 Reads
11.814 Impact Factor

Angiotensin-converting enzyme overexpression in myelocytes enhances the immune response.

Biol Chem 2014 Oct;395(10):1173-8

Angiotensin-converting enzyme (ACE) plays an important role in blood pressure control. ACE also has effects on renal function, reproduction, hematopoiesis, and several aspects of the immune response. ACE 10/10 mice overexpress ACE in monocytic cells; macrophages from ACE 10/10 mice demonstrate increased polarization toward a proinflammatory phenotype. As a result, ACE 10/10 mice have a highly effective immune response following challenge with melanoma, bacterial infection, or Alzheimer disease. As shown in ACE 10/10 mice, enhanced monocytic function greatly contributes to the ability of the immune response to defend against a wide variety of antigenic and non-antigenic challenges.

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http://dx.doi.org/10.1515/hsz-2013-0295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312006PMC
October 2014
24 Reads
3.273 Impact Factor

ACE overexpression in myelomonocytic cells: effect on a mouse model of Alzheimer's disease.

Curr Hypertens Rep 2014 Jul;16(7):444

Department of Neurosurgery and the Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.

While it is well known that angiotensin converting enzyme (ACE) plays an important role in blood pressure control, ACE also has effects on renal function, hematopoiesis, reproduction, and aspects of the immune response. ACE 10/10 mice overexpress ACE in myelomonocytic cells. Macrophages from these mice have an increased polarization towards a pro-inflammatory phenotype that results in a very effective immune response to challenge by tumors or bacterial infection. In a mouse model of Alzheimer's disease (AD), the ACE 10/10 phenotype provides significant protection against AD pathology, including reduced inflammation, reduced burden of the neurotoxic amyloid-? protein and preserved cognitive function. Taken together, these studies show that increased myelomonocytic ACE expression in mice alters the immune response to better defend against many different types of pathologic insult, including the cognitive decline observed in an animal model of AD.

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http://dx.doi.org/10.1007/s11906-014-0444-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051235PMC
July 2014
12 Reads
3.606 Impact Factor

T-Lymphocyte Deficiency Exacerbates Behavioral Deficits in the 6-OHDA Unilateral Lesion Rat Model for Parkinson's Disease.

J Neurol Neurophysiol 2014 May;5(3)

Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, 90048, USA, Department of Psychiatry, Cedars-Sinai Medical Center, Los Angeles, California, 90048, USA; Occidental College, Los Angeles, CA 90041, USA.

T-lymphocytes have been previously implicated in protecting dopaminergic neurons in the substantianigra from induced cell death. However, the role of T-cells in neurodegenerative models such as Parkinson's disease (PD) has not been fully elucidated. To examine the role of T-lymphocytes on motor behavior in the 6-hydroxydopamine (6-OHDA) unilateral striatal partial lesion PD rat model, we assessed progression of hemi-parkinsonian lesions in the substantia nigra, induced by 6-OHDA striatal injections, in athymic rats (RNU-/-, T-lymphocyte-deficient) as compared to RNU-/+ rats (phenotypically normal). Motor skills were determined by the cylinder and D-amphetamine sulfate-induced rotational behavioral tests. Cylinder behavioral test showed no significant difference between unilaterally lesioned RNU-/- and RNU-/+ rats. However both unilaterally lesioned RNU-/- and RNU-/+ rats favored the use of the limb ipsilateral to lesion. Additionally, amphetamine-induced rotational test revealed greater rotational asymmetry in RNU-/- rats compared to RNU-/+ rats at two- and six-week post-lesion. Quantitative immunohistochemistry confirmed loss of striatal TH-immunopositive fibers in RNU-/- and RNU-/+ rat, as well as blood-brain-barrier changes associated with PD that may influence passage of immune cells into the central nervous system in RNU-/- brains. Specifically, GFAP immunopositive cells were decreased, as were astrocytic end-feet (AQP4) contacting blood vessels (laminin) in the lesioned relative to contralateral striatum. Flow cytometric analysis in 6-OHDA lesioned RNU-/+rats revealed increased CD4+ and decreased CD8+ T cells specifically within lesioned brain. These results suggest that both major T cell subpopulations are significantly and reciprocally altered following 6-OHDA-lesioning, and that global T cell deficiency exacerbates motor behavioral defects in this rat model of PD.

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http://dx.doi.org/10.4172/2155-9562.1000209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207300PMC
May 2014
34 Reads
1.260 Impact Factor

Alzheimer's disease in the retina: imaging retinal aβ plaques for early diagnosis and therapy assessment.

Neurodegener Dis 2012 10;10(1-4):285-93. Epub 2012 Feb 10.

Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Los Angeles, Calif, USA.

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http://dx.doi.org/10.1159/000335154DOI Listing
August 2012
26 Reads
37 Citations
3.511 Impact Factor

Abnormal changes in NKT cells, the IGF-1 axis, and liver pathology in an animal model of ALS.

PLoS One 2011 2;6(8):e22374. Epub 2011 Aug 2.

Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel.

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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022374PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149057PMC
December 2011
14 Reads
21 Citations
3.234 Impact Factor

Egr1 expression is induced following glatiramer acetate immunotherapy in rodent models of glaucoma and Alzheimer's disease.

Invest Ophthalmol Vis Sci 2011 Nov 21;52(12):9033-46. Epub 2011 Nov 21.

Department of Ophthalmology, Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA.

Purpose: Immunization with glatiramer acetate (GA) alleviates the neuropathology associated with glaucoma and Alzheimer's disease (AD) in rodent models. This research was undertaken to screen for molecular factors underlying GA-induced neuroprotective mechanisms in these models of chronic neurodegeneration.

Methods: Gene expression profiles were analyzed in GA-immunized versus nonimmunized elevated-intraocular pressure (IOP) rat models of glaucoma by using whole genome cDNA microarrays and were further validated by quantitative real-time PCR analysis. A gene, prominently upregulated by GA in elevated IOP retina, was further studied in APP(SWE)/PS1(?E9)-transgenic (AD-Tg) mice after GA immunization.

Results: Seven days after treatment with GA, numerous genes were regulated in the retinas of rats with elevated IOP. Comprehensive functional classification and DAVID/KEGG enrichment analysis of GA-induced differentially expressed genes revealed annotation terms and pathways involved in neuroprotection, immune responses, cell communication, and regeneration. Specifically, increased mRNA levels of an early growth response (Egr) 1 gene were evident in GA-immunized retinas with elevated IOP. In AD-Tg mice, a significant increase in hippocampal EGR1 protein levels was also found in response to GA immunization. Nuclear EGR1 in the dentate gyrus colocalized more frequently with doublecortin-positive and Ki67 proliferating neural progenitors in GA-immunized as compared to nonimmunized AD-Tg mice. Further, EGR1 levels were negatively correlated with hippocampal amyloid-? plaque burden.

Conclusions: This study presents global gene expression profiles associated with GA immunization in a glaucoma rat model. Moreover, it identifies EGR1 transcription factor as a potential mediator for GA-induced neuroprotection in both glaucoma and AD.

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http://dx.doi.org/10.1167/iovs.11-7498DOI Listing
November 2011
20 Reads
3.812 Impact Factor

Identification of amyloid plaques in retinas from Alzheimer's patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model.

Neuroimage 2011 Jan 13;54 Suppl 1:S204-17. Epub 2010 Jun 13.

Department of Neurosurgery and Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Noninvasive monitoring of ?-amyloid (A?) plaques, the neuropathological hallmarks of Alzheimer's disease (AD), is critical for AD diagnosis and prognosis. Current visualization of A? plaques in brains of live patients and animal models is limited in specificity and resolution. The retina as an extension of the brain presents an appealing target for a live, noninvasive optical imaging of AD if disease pathology is manifested there. We identified retinal A? plaques in postmortem eyes from AD patients (n=8) and in suspected early stage cases (n=5), consistent with brain pathology and clinical reports; plaques were undetectable in age-matched non-AD individuals (n=5). In APP(SWE)/PS1(?E9) transgenic mice (AD-Tg; n=18) but not in non-Tg wt mice (n=10), retinal A? plaques were detected following systemic administration of curcumin, a safe plaque-labeling fluorochrome. Moreover, retinal plaques were detectable earlier than in the brain and accumulated with disease progression. An immune-based therapy effective in reducing brain plaques, significantly reduced retinal A? plaque burden in immunized versus non-immunized AD mice (n=4 mice per group). In live AD-Tg mice (n=24), systemic administration of curcumin allowed noninvasive optical imaging of retinal A? plaques in vivo with high resolution and specificity; plaques were undetectable in non-Tg wt mice (n=11). Our discovery of A? specific plaques in retinas from AD patients, and the ability to noninvasively detect individual retinal plaques in live AD mice establish the basis for developing high-resolution optical imaging for early AD diagnosis, prognosis assessment and response to therapies.

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http://dx.doi.org/10.1016/j.neuroimage.2010.06.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2991559PMC
January 2011
44 Reads
6.943 Impact Factor

Thymic involution, a co-morbidity factor in amyotrophic lateral sclerosis.

J Cell Mol Med 2010 Oct;14(10):2470-82

Maxine-Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Amyotrophic lateral sclerosis (ALS) is a devastating disease, characterized by extremely rapid loss of motor neurons. Our studies over the last decade have established CD4(+) T cells as important players in central nervous system maintenance and repair. Those results, together with recent findings that CD4(+) T cells play a protective role in mouse models of ALS, led us to the current hypothesis that in ALS, a rapid T-cell malfunction may develop in parallel to the motor neuron dysfunction. Here, we tested this hypothesis by assessing thymic function, which serves as a measure of peripheral T-cell availability, in an animal model of ALS (mSOD1 [superoxide dismutase] mice; G93A) and in human patients. We found a significant reduction in thymic progenitor-cell content, and abnormal thymic histology in 3-4-month-old mSOD1 mice. In ALS patients, we found a decline in thymic output, manifested in the reduction in blood levels of T-cell receptor rearrangement excision circles, a non-invasive measure of thymic function, and demonstrated a restricted T-cell repertoire. The morbidity of the peripheral immune cells was also manifested in the increase of pro-apoptotic BAX/BCXL2 expression ratio in peripheral blood mononuclear cells (PBMCs) of these patients. In addition, gene expression screening in the same PBMCs, revealed in the ALS patients a reduction in key genes known to be associated with T-cell activity, including: CD80, CD86, IFNG and IL18. In light of the reported beneficial role of T cells in animal models of ALS, the present observation of thymic dysfunction, both in human patients and in an animal model, might be a co-pathological factor in ALS, regardless of the disease aetiology. These findings may lead to the development of novel therapeutic approaches directed at overcoming the thymic defect and T-cell deficiency.

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http://dx.doi.org/10.1111/j.1582-4934.2009.00863.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3823164PMC
October 2010
31 Reads
4.658 Impact Factor

Attenuation of AD-like neuropathology by harnessing peripheral immune cells: local elevation of IL-10 and MMP-9.

J Neurochem 2009 Dec 24;111(6):1409-24. Epub 2009 Sep 24.

Department of Neurosurgery, the Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angels, California 90048, USA.

Immunization with an altered myelin-derived peptide (MOG45D) improves recovery from acute CNS insults, partially via recruitment of monocyte-derived macrophages that locally display a regulatory activity. Here, we investigated the local alterations in the cellular and molecular immunological milieu associated with attenuation of Alzheimer's disease-like pathology following immunotherapy. We found that immunization of amyloid precursor protein/presenilin 1 double-transgenic mice with MOG45D peptide, loaded on dendritic cells, led to a substantial reduction of parenchymal and perivascular amyloid beta (Abeta)-plaque burden and soluble Abeta((1-42)) peptide levels as well as reduced astrogliosis and levels of a key glial scar protein (chondroitin sulphate proteoglycan). These changes were associated with a shift in the local innate immune response, manifested by increased Iba1+/CD45(high) macrophages that engulfed Abeta, reduced pro-inflammatory (tumor necrosis factor-alpha) and increased anti-inflammatory (interleukin-10) cytokines, as well as a significant increase in growth factors (IGF-1 and TGFbeta) in the brain. Furthermore, the levels of matrix metalloproteinase-9, an enzyme shown to degrade Abeta and is associated with glial scar formation, were significantly elevated in the brain following immunization. Altogether, these results indicate that boosting systemic immune cells leads to a local immunomodulation manifested by elevated levels of anti-inflammatory cytokines and metalloproteinases that contribute to ameliorating Alzheimer's disease pathology.

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http://dx.doi.org/10.1111/j.1471-4159.2009.06402.xDOI Listing
December 2009
23 Reads
4.870 Impact Factor

Selective ablation of bone marrow-derived dendritic cells increases amyloid plaques in a mouse Alzheimer's disease model.

Eur J Neurosci 2007 Jul 10;26(2):413-6. Epub 2007 Jul 10.

Department of Neurobiology, The Weizmann Institute of Science, 76100 Rehovot, Israel.

We have recently shown that the ability of microglia to effectively fight off aggregated beta-amyloid plaque formation and cognitive loss in transgenic mouse models of Alzheimer's disease (Tg-AD), is augmented in response to T-cell-based immunization, using glatiramer acetate (GA). The immunization increases incidence of local CD11c+ dendritic-like cells. It is unclear, however, whether these dendritic cells are derived from resident microglia or from the bone marrow. To determine the origin of this dendritic-cell population, we used chimeric mice whose bone marrow-derived cells express a transgene that allows the cells to be specifically ablated by diphtheria toxin. We show here that T-cell-based immunization of these mice, using GA, induced the recruitment of bone marrow-derived dendritic cells. Depletion of the dendritic cells by systemic injection of diphtheria toxin resulted in significantly increased formation of amyloid plaques. Thus, recruitment of bone marrow-derived dendritic cells evidently plays a role in reducing plaque formation in a mouse model of Alzheimer's disease.

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http://dx.doi.org/10.1111/j.1460-9568.2007.05652.xDOI Listing
July 2007
13 Reads
4.350 Impact Factor

Dual contribution of NR2B subunit of NMDA receptor and SK3 Ca(2+)-activated K+ channel to genetic predisposition to anorexia nervosa.

J Psychiatr Res 2007 Jan-Feb;41(1-2):160-7. Epub 2005 Sep 12.

The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer 52621, Israel.

Since identification of the genetic component in anorexia nervosa (AN), genes that partake in serotonergic and dopaminergic systems and in hormonal and weight regulation have been suggested as potential candidates for AN susceptibility. We propose another set of candidate genes. Those are genes that are involved in the signaling pathway using NMDA-R and SK channels and have been suggested as possible effectors of NMDA-R driven signaling. The role of NMDA-R in the etiology of schizophrenia has already been substantiated on various levels. Several studies based on population and family groups have implicated SK3 in schizophrenia and more recently in AN as well. Our study group consisted of 90 AN family trios. We examined the transmission of two potentially functional polymorphisms, 5073T>G polymorphism in the gene encoding the NR2B subunit of NMDA-R and CAG repeats in the coding region of SK3 channel gene. Using HHRR and TDT approaches, we found that both polymorphisms were preferentially transmitted to AN offspring (TDT yielded chi(2)=5.01, p=0.025 for NR2B 5073G alleles and chi(2)=11.75, p<0.001 for SK3 L alleles including >19 repeats). Distribution analysis of the combined NR2B/SK3 genotypes suggests that the contribution of both polymorphisms to AN risk is independent and cumulative (OR=2.44 for NR2B GG genotype and OR=3.01 for SK3 SL and LL genotypes, and OR=6.8 for the combined NR2B/SK3 genotypes including high-risk alleles). These findings point to the contribution of genes associated with the NMDA-R signaling pathway to predisposition and development of AN.

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https://linkinghub.elsevier.com/retrieve/pii/S00223956050009
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http://dx.doi.org/10.1016/j.jpsychires.2005.07.010DOI Listing
February 2007
38 Reads
4.461 Impact Factor

Glatiramer acetate fights against Alzheimer's disease by inducing dendritic-like microglia expressing insulin-like growth factor 1.

Proc Natl Acad Sci U S A 2006 Aug 24;103(31):11784-9. Epub 2006 Jul 24.

Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.

Alzheimer's disease (AD) is characterized by plaque formation, neuronal loss, and cognitive decline. The functions of the local and systemic immune response in this disease are still controversial. Using AD double-transgenic (APP/PS1) mice, we show that a T cell-based vaccination with glatiramer acetate, given according to a specific regimen, resulted in decreased plaque formation and induction of neurogenesis. It also reduced cognitive decline, assessed by performance in a Morris water maze. The vaccination apparently exerted its effect by causing a phenotype switch in brain microglia to dendritic-like (CD11c) cells producing insulin-like growth factor 1. In vitro findings showed that microglia activated by aggregated beta-amyloid, and characterized as CD11b(+)/CD11c(-)/MHC class II(-)/TNF-alpha(+) cells, impeded neurogenesis from adult neural stem/progenitor cells, whereas CD11b(+)/CD11c(+)/MHC class II(+)/TNF-alpha(-) microglia, a phenotype induced by IL-4, counteracted the adverse beta-amyloid-induced effect. These results suggest that dendritic-like microglia, by facilitating the necessary adjustment, might contribute significantly to the brain's resistance to AD and argue against the use of antiinflammatory drugs.

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http://dx.doi.org/10.1073/pnas.0604681103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1544247PMC
August 2006
12 Reads
10.220 Impact Factor

CAG repeat polymorphism within the KCNN3 gene is a significant contributor to susceptibility to anorexia nervosa: a case-control study of female patients and several ethnic groups in the Israeli Jewish population.

Am J Med Genet B Neuropsychiatr Genet 2004 Nov;131B(1):76-80

Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel.

The human small-conductance Ca(2+)-activated potassium channel gene KCNN3 has been involved in mechanisms underlying neuronal function and plasticity. A multiallelic CAG repeat polymorphism within the KCNN3 has been associated with schizophrenia and bipolar disorder. We have previously reported in a family-based study that longer CAG repeats are preferentially transmitted to patients with anorexia nervosa (AN). The present study extends the analysis of KCNN3 allele distribution to a larger series of AN female patients and control groups, incorporating information on ethnicity and co-morbidities associated with AN. The data analysis is presented while considering separately the two alleles of each individual, namely a minor (shorter) and a major (longer) allele. This study has found that the KCNN3 allele distribution in the general Israeli population does not differ significantly in at least four Jewish ethnic groups of Ashkenazi, North African, Iraqi, and Yemenite origin. These have been used as control groups in a matched case-control analysis that has demonstrated a significant over-representation of KCNN3 alleles with longer CAG repeats among AN patients (P < 0.001 for the major allele and P = 0.035 for allele sum). Under dichotomization, a significantly higher prevalence of the L allele (>19 repeats) has been observed among AN patients (P < 0.001). While considering AN and co-morbid phenotypes, a tendency towards longer (L) alleles has been observed in the subset of patients with obsessive-compulsive disorder (OCD) co-morbidity. These findings further implicate KCNN3 as a significant contributor to predisposition to AN.

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http://dx.doi.org/10.1002/ajmg.b.20154DOI Listing
November 2004
14 Reads
3.416 Impact Factor

Association study of CAG repeats in the KCNN3 gene in Israeli patients with major psychosis.

Psychiatr Genet 2003 Sep;13(3):143-50

Sha'ar Menashe Mental Health Center, Mobile Post Hefer 38814, Hadera, Israel.

Objectives: Several studies reported contradictory findings regarding the association of major psychosis with CAG repeats in the KCNN3 gene. We investigated the contribution of the CAG repeat at the KCNN3 gene, localized to chromosome 1q21.3, to the genetic susceptibility for schizophrenia, schizoaffective and bipolar disorders.

Methods: Analysis of the number of CAG repeats and the differences in allele length were performed for Israeli Ashkenazi Jews, non-Ashkenazi Jews, and Arabs diagnosed with major psychosis (n=181) versus matched ethnic controls (n=207).

Results: We found no significant difference in the number of CAG repeats between the entire sample of patients and controls. However, an analysis of the differences of allele length revealed a significantly greater number of patients with identical allele length (43.1%) when compared with normal controls (30.4%). Furthermore, an earlier age of non-paranoid schizophrenia onset was found associated with differences in allele sizes. There were no significant differences in the number of CAG repeats and the differences in allele length when subjects were grouped according to gender, ethnic origins of their parents, family history, and diagnostic groups.

Conclusions: Our results support the hypothesis that a contribution of the KCNN3 gene to genetic susceptibility to major psychosis and their phenotypic polymorphism may be related to the difference of allele length rather than to the number of CAG repeats.

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http://pdfs.journals.lww.com/psychgenetics/2003/09000/Associ
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http://dx.doi.org/10.1097/00041444-200309000-00002DOI Listing
September 2003
11 Reads
2.414 Impact Factor

Association between anorexia nervosa and the hsKCa3 gene: a family-based and case control study.

Mol Psychiatry 2002 ;7(1):82-5

The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel.

Familial and twin studies have suggested that anorexia nervosa (AN) is a multifactorial disorder with a substantial genetic contribution. The hSKCa3 potassium channel gene, which contains polymorphic CAG repeats in the coding region and is involved in the regulation of neuronal activity, may be a candidate gene for AN because alleles with longer repeats have been found to be associated with mental disorders. Forty Israeli AN family trios were genotyped for the hSKCa3 CAG repeat polymorphism using the haplotype relative risk (HRR) method. The distribution of alleles transmitted to the patients was found to be significantly different from that of the non-transmitted parental alleles, with the longer alleles being over-represented in the patients (Wilcoxon rank test, P = 0.008). The transmission disequilibrium test (TDT) revealed that longer (>19) repeat alleles were preferentially transmitted to AN patients (McNemar's chi(2) = 10.31, P = 0.0013). These results were corroborated by comparing the distribution of alleles between patients and healthy controls (Mann-Whitney test, P = 0.005). Our study suggests that the longer repeat alleles of the hSKCa3 gene may contribute to the genetic susceptibility to AN.

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http://dx.doi.org/10.1038/sj.mp.4000931DOI Listing
April 2002
9 Reads
14.496 Impact Factor

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Keith L Black
Keith L Black

Maxine Dunitz Neurosurgical Institute

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Andrea Vergallo
Andrea Vergallo

University of Pisa

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Simone Lista
Simone Lista

Université Pierre et Marie Curie

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Harald Hampel
Harald Hampel

Sorbonne Universités

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Julia Sheyn
Julia Sheyn

Maxine-Dunitz Neurosurgical Institute

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Marie-Odile Habert

Université Pierre et Marie Curie-Paris 6

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Bruno Dubois

Sorbonne Universités

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University of California at Los Angeles

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The Weizmann Institute of Science

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