Publications by authors named "Robert Vassar"

83 Publications

A promising new γ-secretase modulator for Alzheimer's disease.

J Exp Med 2021 Apr;218(4)

Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL.

Effective and safe treatments for Alzheimer's disease (AD) have been an elusive target for scientists who have been working tirelessly to gain control over a disease that is affecting millions of people, with continually rising case numbers as the population ages. However, in this issue of JEM, Rynearson et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20202560) present a beacon of hope for this field with a preclinical evaluation of a potent and robust γ-secretase modulator (GSM).
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http://dx.doi.org/10.1084/jem.20210077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944409PMC
April 2021

Early detection and personalized medicine: Future strategies against Alzheimer's disease.

Prog Mol Biol Transl Sci 2021 3;177:157-173. Epub 2020 Dec 3.

Department of Neurology, Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States. Electronic address:

Alzheimer's disease (AD) is the leading cause of dementia and sixth cause of death in elderly adults. AD poses a huge economic burden on society and constitutes an unprecedented challenge for caregivers and families affected. Aging of the population is projected to drastically aggravate the situation in the near future. To date, no therapy is available to prevent or ameliorate the disease. Moreover, several clinical trials for promising therapeutic agents have failed. Lack of supporting biomarker data for pre-symptomatic enrollment and inaccurate stratification of patients based on genetic heterogeneity appear to be contributing factors to this lack of success. Recently, the treatment of cancer has seen enormous advances based on the personalized genetics and biomarkers of the individual patient, forming the foundation of precision medicine for cancer. Likewise, technological progress in AD biomarker research promises the availability of reliable assays for pathology staging on a routine basis relatively soon. Moreover, tremendous achievements in AD genetics and high-throughput genotyping technology allow identification of predisposing risk alleles accurately and on a large scale. Finally, availability of electronic health records (EHR) promises the opportunity to integrate biomarker, genomic and clinical data efficiently. Together, these advances will form the basis of precision medicine for AD.
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http://dx.doi.org/10.1016/bs.pmbts.2020.10.002DOI Listing
December 2020

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis.

JAMA Neurol 2021 Jan;78(1):102-113

National Alzheimer's Coordinating Center, University of Washington, Seattle.

Importance: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated.

Objective: To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel.

Design, Setting, And Participants: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019.

Main Outcomes And Measures: Diagnosis of Alzheimer disease.

Results: A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration.

Conclusions And Relevance: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.
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http://dx.doi.org/10.1001/jamaneurol.2020.3536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573798PMC
January 2021

Aβ-accelerated neurodegeneration caused by Alzheimer's-associated variant R1279Q is rescued by angiotensin system inhibition in mice.

Sci Transl Med 2020 09;12(563)

Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

Recent genome-wide association studies identified the angiotensin-converting enzyme gene () as an Alzheimer's disease (AD) risk locus. However, the pathogenic mechanism by which causes AD is unknown. Using whole-genome sequencing, we identified rare coding variants in AD families and investigated one, ACE1 R1279Q, in knockin (KI) mice. Similar to AD, ACE1 was increased in neurons, but not microglia or astrocytes, of KI brains, which became elevated further with age. Angiotensin II (angII) and angII receptor AT1R signaling were also increased in KI brains. Autosomal dominant neurodegeneration and neuroinflammation occurred with aging in KI hippocampus, which were absent in the cortex and cerebellum. Female KI mice exhibited greater hippocampal electroencephalograph disruption and memory impairment compared to males. variant effects were more pronounced in female KI mice, suggesting a mechanism for higher AD risk in women. Hippocampal neurodegeneration was completely rescued by treatment with brain-penetrant drugs that inhibit ACE1 and AT1R. Although variant-induced neurodegeneration did not depend on β-amyloid (Aβ) pathology, amyloidosis in 5XFAD mice crossed to KI mice accelerated neurodegeneration and neuroinflammation, whereas Aβ deposition was unchanged. KI mice had normal blood pressure and cerebrovascular functions. Our findings strongly suggest that increased ACE1/angII signaling causes aging-dependent, Aβ-accelerated selective hippocampal neuron vulnerability and female susceptibility, hallmarks of AD that have hitherto been enigmatic. We conclude that repurposed brain-penetrant ACE inhibitors and AT1R blockers may protect against AD.
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http://dx.doi.org/10.1126/scitranslmed.aaz2541DOI Listing
September 2020

The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease.

Nature 2020 10 2;586(7831):735-740. Epub 2020 Sep 2.

Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Innate immunity is associated with Alzheimer's disease, but the influence of immune activation on the production of amyloid-β is unknown. Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-β. Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to γ-secretase and upregulates its activity, thereby increasing the production of amyloid-β. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer's disease genes. Furthermore, knockout of IFITM3 reduces γ-secretase activity and the formation of amyloid plaques in a transgenic mouse model (5xFAD) of early amyloid deposition. IFITM3 protein is upregulated in tissue samples from a subset of patients with late-onset Alzheimer's disease that exhibit higher γ-secretase activity. The amount of IFITM3 in the γ-secretase complex has a strong and positive correlation with γ-secretase activity in samples from patients with late-onset Alzheimer's disease. These findings reveal a mechanism in which γ-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer's disease is thereby increased.
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http://dx.doi.org/10.1038/s41586-020-2681-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919141PMC
October 2020

The β-Secretase BACE1 in Alzheimer's Disease.

Biol Psychiatry 2021 Apr 13;89(8):745-756. Epub 2020 Feb 13.

Neurology Business Group, Eisai Inc., Woodcliff Lake, New Jersey; Sorbonne University, GRC No. 21, Alzheimer Precision Medicine, Pitié-Salpêtrière Hospital, Paris, France; Institute of Memory and Alzheimer's Disease, Department of Neurology, Pitié-Salpêtrière Hospital, Paris, France; Brain & Spine Institute, INSERM U 1127, CNRS UMR 7225, Paris, France. Electronic address:

BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) was initially cloned and characterized in 1999. It is required for the generation of all monomeric forms of amyloid-β (Aβ), including Aβ, which aggregates into bioactive conformational species and likely initiates toxicity in Alzheimer's disease (AD). BACE1 concentrations and rates of activity are increased in AD brains and body fluids, thereby supporting the hypothesis that BACE1 plays a critical role in AD pathophysiology. Therefore, BACE1 is a prime drug target for slowing down Aβ production in early AD. Besides the amyloidogenic pathway, BACE1 has other substrates that may be important for synaptic plasticity and synaptic homeostasis. Indeed, germline and adult conditional BACE1 knockout mice display complex neurological phenotypes. Despite BACE1 inhibitor clinical trials conducted so far being discontinued for futility or safety reasons, BACE1 remains a well-validated therapeutic target for AD. A safe and efficacious compound with high substrate selectivity as well as a more accurate dose regimen, patient population, and disease stage may yet be found. Further research should focus on the role of Aβ and BACE1 in physiological processes and key pathophysiological mechanisms of AD. The functions of BACE1 and the homologue BACE2, as well as the biology of Aβ in neurons and glia, deserve further investigation. Cellular and molecular studies of BACE1 and BACE2 knockout mice coupled with biomarker-based human research will help elucidate the biological functions of these important enzymes and identify their substrates and downstream effects. Such studies will have critical implications for BACE1 inhibition as a therapeutic approach for AD.
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http://dx.doi.org/10.1016/j.biopsych.2020.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533042PMC
April 2021

Contribution of GABAergic interneurons to amyloid-β plaque pathology in an APP knock-in mouse model.

Mol Neurodegener 2020 01 8;15(1). Epub 2020 Jan 8.

VIB Center for Brain & Disease Research, Leuven, Belgium.

The amyloid-β (Aβ) peptide, the primary constituent of amyloid plaques found in Alzheimer's disease (AD) brains, is derived from sequential proteolytic processing of the Amyloid Precursor Protein (APP). However, the contribution of different cell types to Aβ deposition has not yet been examined in an in vivo, non-overexpression system. Here, we show that endogenous APP is highly expressed in a heterogeneous subset of GABAergic interneurons throughout various laminae of the hippocampus, suggesting that these cells may have a profound contribution to AD plaque pathology. We then characterized the laminar distribution of amyloid burden in the hippocampus of an APP knock-in mouse model of AD. To examine the contribution of GABAergic interneurons to plaque pathology, we blocked Aβ production specifically in these cells using a cell type-specific knock-out of BACE1. We found that during early stages of plaque deposition, interneurons contribute to approximately 30% of the total plaque load in the hippocampus. The greatest contribution to plaque load (75%) occurs in the stratum pyramidale of CA1, where plaques in human AD cases are most prevalent and where pyramidal cell bodies and synaptic boutons from perisomatic-targeting interneurons are located. These findings reveal a crucial role of GABAergic interneurons in the pathology of AD. Our study also highlights the necessity of using APP knock-in models to correctly evaluate the cellular contribution to amyloid burden since APP overexpressing transgenic models drive expression in cell types according to the promoter and integration site and not according to physiologically relevant expression mechanisms.
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http://dx.doi.org/10.1186/s13024-019-0356-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950898PMC
January 2020

Death by microglia.

J Exp Med 2019 11 23;216(11):2451-2452. Epub 2019 Oct 23.

Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL

The roles of microglia and ApoE in tauopathies, such as Alzheimer's disease, remain elusive. In this issue, Shi et al. (https://doi.org/10.1084/jem.20190980) demonstrate that microglia-mediated innate immunity collaborates with ApoE to drive neurodegeneration and disease progression in a mouse model of tauopathy.
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http://dx.doi.org/10.1084/jem.20191536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829604PMC
November 2019

RPS23RG1 May Prevent Ubiquitin-Proteosomal Degradation of Postsynaptic Densities-93 and -95 to Protect Synaptic Function: Implications for Alzheimer's Disease.

Biol Psychiatry 2019 08;86(3):164-166

Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

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http://dx.doi.org/10.1016/j.biopsych.2019.06.004DOI Listing
August 2019

Modeling genetic diversity in Alzheimer's disease.

Lab Anim (NY) 2019 03;48(3):87-88

Dept. of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, USA.

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http://dx.doi.org/10.1038/s41684-019-0248-3DOI Listing
March 2019

3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice.

J Exp Med 2019 02 15;216(2):279-293. Epub 2019 Jan 15.

Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA

3K3A-activated protein C (APC), a cell-signaling analogue of endogenous blood serine protease APC, exerts vasculoprotective, neuroprotective, and anti-inflammatory activities in rodent models of stroke, brain injury, and neurodegenerative disorders. 3K3A-APC is currently in development as a neuroprotectant in patients with ischemic stroke. Here, we report that 3K3A-APC inhibits BACE1 amyloidogenic pathway in a mouse model of Alzheimer's disease (AD). We show that a 4-mo daily treatment of 3-mo-old 5XFAD mice with murine recombinant 3K3A-APC (100 µg/kg/d i.p.) prevents development of parenchymal and cerebrovascular amyloid-β (Aβ) deposits by 40-50%, which is mediated through NFκB-dependent transcriptional inhibition of BACE1, resulting in blockade of Aβ generation in neurons overexpressing human Aβ-precursor protein. Consistent with reduced Aβ deposition, 3K3A-APC normalized hippocampus-dependent behavioral deficits and cerebral blood flow responses, improved cerebrovascular integrity, and diminished neuroinflammatory responses. Our data suggest that 3K3A-APC holds potential as an effective anti-Aβ prevention therapy for early-stage AD.
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http://dx.doi.org/10.1084/jem.20181035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363429PMC
February 2019

A promising, novel, and unique BACE1 inhibitor emerges in the quest to prevent Alzheimer's disease.

EMBO Mol Med 2018 11;10(11)

Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

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http://dx.doi.org/10.15252/emmm.201809717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220261PMC
November 2018

ER stress is not elevated in the 5XFAD mouse model of Alzheimer's disease.

J Biol Chem 2018 11 12;293(48):18434-18443. Epub 2018 Oct 12.

From the Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

Alzheimer's disease mouse models that overexpress amyloid precursor protein (APP) and presenilin 1 (PS1) form β-amyloid (Aβ) plaques, a hallmark Alzheimer's disease lesion. It has been assumed that the neuroinflammation, synaptic dysfunction, neurodegeneration, and cognitive impairment observed in these mice are caused by cerebral Aβ accumulation. However, it is also possible that accumulation of the overexpressed transmembrane proteins APP and PS1 in the endoplasmic reticulum (ER) triggers chronic ER stress and activation of the unfolded protein response (UPR). The 5XFAD mouse, a widely used amyloid pathology model, overexpresses APP and PS1, displays aggressive amyloid pathology, and has been reported to exhibit ER stress. To systematically evaluate whether 5XFAD mice have increased ER stress, here we used biochemical approaches to assess a comprehensive panel of UPR markers. We report that APP and PS1 levels are 1.8- and 1.5-fold, respectively, of those in 5XFAD compared with nontransgenic brains, indicating that transgenes are not massively overexpressed in 5XFAD mice. Using immunoblotting, we quantified UPR protein levels in nontransgenic, 5XFAD, and 5XFAD;BACE1 mice at 4, 6, and 9 months of age. Importantly, we did not observe elevation of the ER stress markers p-eIF2α, ATF4, CHOP, p-IRE1α, or BiP at any age in 5XFAD or 5XFAD;BACE1 compared with nontransgenic mice. Despite lacking Aβ generation, 5XFAD;BACE1 mice still expressed APP and PS1 transgenes, indicating that their overexpression does not cause ER stress. These results reveal the absence of ER stress in 5XFAD mice, suggesting that artifactual phenotypes associated with overexpression-induced ER stress are not a concern in this model.
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http://dx.doi.org/10.1074/jbc.RA118.005769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290164PMC
November 2018

Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice.

Sci Transl Med 2018 09;10(459)

Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

β-Site APP (amyloid precursor protein) cleaving enzyme 1 (BACE1) is the β-secretase enzyme that initiates production of the toxic amyloid-β peptide that accumulates in the brains of patients with Alzheimer's disease (AD). Hence, BACE1 is a prime therapeutic target, and several BACE1 inhibitor drugs are currently being tested in clinical trials for AD. However, the safety of BACE1 inhibition is unclear. Germline BACE1 knockout mice have multiple neurological phenotypes, although these could arise from BACE1 deficiency during development. To address this question, we report that tamoxifen-inducible conditional BACE1 knockout mice in which the gene was ablated in the adult largely lacked the phenotypes observed in germline BACE1 knockout mice. However, one BACE1-null phenotype was induced after gene deletion in the adult mouse brain. This phenotype showed reduced length and disorganization of the hippocampal mossy fiber infrapyramidal bundle, the axonal pathway of dentate gyrus granule cells that is maintained by neurogenesis in the mouse brain. This defect in axonal organization correlated with reduced BACE1-mediated cleavage of the neural cell adhesion protein close homolog of L1 (CHL1), which has previously been associated with axon guidance. Although our results indicate that BACE1 inhibition in the adult mouse brain may avoid phenotypes associated with BACE1 deficiency during embryonic and postnatal development, they also suggest that BACE1 inhibitor drugs developed for treating AD may disrupt the organization of an axonal pathway in the hippocampus, an important structure for learning and memory.
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http://dx.doi.org/10.1126/scitranslmed.aao5620DOI Listing
September 2018

Store depletion-induced h-channel plasticity rescues a channelopathy linked to Alzheimer's disease.

Neurobiol Learn Mem 2018 10 12;154:141-157. Epub 2018 Jun 12.

Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA. Electronic address:

Voltage-gated ion channels are critical for neuronal integration. Some of these channels, however, are misregulated in several neurological disorders, causing both gain- and loss-of-function channelopathies in neurons. Using several transgenic mouse models of Alzheimer's disease (AD), we find that sub-threshold voltage signals strongly influenced by hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels progressively deteriorate over chronological aging in hippocampal CA1 pyramidal neurons. The degraded signaling via HCN channels in the transgenic mice is accompanied by an age-related global loss of their non-uniform dendritic expression. Both the aberrant signaling via HCN channels and their mislocalization could be restored using a variety of pharmacological agents that target the endoplasmic reticulum (ER). Our rescue of the HCN channelopathy helps provide molecular details into the favorable outcomes of ER-targeting drugs on the pathogenesis and synaptic/cognitive deficits in AD mouse models, and implies that they might have beneficial effects on neurological disorders linked to HCN channelopathies.
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http://dx.doi.org/10.1016/j.nlm.2018.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434702PMC
October 2018

BACE1 Mediates HIV-Associated and Excitotoxic Neuronal Damage Through an APP-Dependent Mechanism.

J Neurosci 2018 05 9;38(18):4288-4300. Epub 2018 Apr 9.

Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104,

HIV-associated neurocognitive disorders (HANDs) share common symptoms with Alzheimer's disease (AD), which is characterized by amyloid-β (Aβ) plaques. Plaques are formed by aggregation of Aβ oligomers, which may be the toxic species in AD pathogenesis, and oligomers are generated by cleavage of amyloid precursor protein (APP) by β-site amyloid precursor protein cleaving enzyme 1 (BACE1). BACE1 inhibitors reverse neuronal loss and cognitive decline in animal models of AD. Although studies have also found evidence of altered APP processing in HIV patients, it is unknown whether increased BACE1 expression or Aβ oligomer production is a common neuropathological feature of HAND. Moreover, it is unknown whether BACE1 or APP is involved in the excitotoxic, NMDAR-dependent component of HIV-associated neurotoxicity Herein, we hypothesize that HIV-associated neurotoxicity is mediated by NMDAR-dependent elevation of BACE1 and subsequent altered processing of APP. Supporting this, we observed elevated levels of BACE1 and Aβ oligomers in CNS of male and female HIV patients. In a model of HIV-associated neurotoxicity in which rat neurons are treated with supernatants from HIV-infected human monocyte-derived macrophages, we observed NMDAR-dependent elevation of BACE1 protein. NMDA treatment also increased BACE1 and both pharmacological BACE1 inhibition and genetic loss of APP were partially neuroprotective. Moreover, in APP knock-out (APP) mouse neurons, NMDA-induced toxicity was BACE1 independent, indicating that cytotoxicity of BACE1 is dependent upon APP cleavage. Our findings suggest that increased BACE1 and the resultant Aβ oligomer production may contribute to HIV-associated neuropathogenesis and inhibition of BACE1 could have therapeutic potential in HANDs. HIV-associated neurocognitive disorders (HANDs) represent a range of cognitive impairments affecting ∼50% of HIV individuals. The specific causes of HAND are unknown, but evidence suggests that HIV-infected macrophage infiltration into the brain may cause neuronal damage. Herein, we show that neurons treated with conditioned media from HIV-infected macrophages have increased expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), a protein implicated in Alzheimer's disease pathogenesis. Moreover, inhibition of BACE1 prevented neuronal loss after conditioned media exposure, but had no effect on HIV-associated neurotoxicity in neurons lacking its cleavage target amyloid precursor protein. We also observed increased BACE1 expression in HIV patient brain tissue, confirming the potential relevance of BACE1 as a therapeutic target in HANDs.
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http://dx.doi.org/10.1523/JNEUROSCI.1280-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932640PMC
May 2018

Seeds of Destruction: New Mechanistic Insights into the Role of Apolipoprotein E4 in Alzheimer's Disease.

Authors:
Robert Vassar

Neuron 2017 12;96(5):953-955

Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address:

Apolipoprotein E4 (apoE4) is the strongest genetic risk factor for Alzheimer's disease. Despite nearly 25 years of research, the mechanism by which apoE4 confers increased risk for Alzheimer's disease remains enigmatic. In this issue of Neuron, Liu et al. (2017) and Huynh et al. (2017) shed new light on this important question.
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http://dx.doi.org/10.1016/j.neuron.2017.11.022DOI Listing
December 2017

A Becn1 mutation mediates hyperactive autophagic sequestration of amyloid oligomers and improved cognition in Alzheimer's disease.

PLoS Genet 2017 Aug 14;13(8):e1006962. Epub 2017 Aug 14.

Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States of America.

Impairment of the autophagy pathway has been observed during the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disorder characterized by abnormal deposition of extracellular and intracellular amyloid β (Aβ) peptides. Yet the role of autophagy in Aβ production and AD progression is complex. To study whether increased basal autophagy plays a beneficial role in Aβ clearance and cognitive improvement, we developed a novel genetic model to hyperactivate autophagy in vivo. We found that knock-in of a point mutation F121A in the essential autophagy gene Beclin 1/Becn1 in mice significantly reduces the interaction of BECN1 with its inhibitor BCL2, and thus leads to constitutively active autophagy even under non-autophagy-inducing conditions in multiple tissues, including brain. Becn1F121A-mediated autophagy hyperactivation significantly decreases amyloid accumulation, prevents cognitive decline, and restores survival in AD mouse models. Using an immunoisolation method, we found biochemically that Aβ oligomers are autophagic substrates and sequestered inside autophagosomes in the brain of autophagy-hyperactive AD mice. In addition to genetic activation of autophagy by Becn1 gain-of-function, we also found that ML246, a small-molecule autophagy inducer, as well as voluntary exercise, a physiological autophagy inducer, exert similar Becn1-dependent protective effects on Aβ removal and memory in AD mice. Taken together, these results demonstrate that genetically disrupting BECN1-BCL2 binding hyperactivates autophagy in vivo, which sequestrates amyloid oligomers and prevents AD progression. The study establishes new approaches to activate autophagy in the brain, and reveals the important function of Becn1-mediated autophagy hyperactivation in the prevention of AD.
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http://dx.doi.org/10.1371/journal.pgen.1006962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570506PMC
August 2017

APP mouse models for Alzheimer's disease preclinical studies.

EMBO J 2017 09 1;36(17):2473-2487. Epub 2017 Aug 1.

Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako, Japan

Animal models of human diseases that accurately recapitulate clinical pathology are indispensable for understanding molecular mechanisms and advancing preclinical studies. The Alzheimer's disease (AD) research community has historically used first-generation transgenic (Tg) mouse models that overexpress proteins linked to familial AD (FAD), mutant amyloid precursor protein (APP), or APP and presenilin (PS). These mice exhibit AD pathology, but the overexpression paradigm may cause additional phenotypes unrelated to AD Second-generation mouse models contain humanized sequences and clinical mutations in the endogenous mouse gene. These mice show Aβ accumulation without phenotypes related to overexpression but are not yet a clinical recapitulation of human AD In this review, we evaluate different APP mouse models of AD, and review recent studies using the second-generation mice. We advise AD researchers to consider the comparative strengths and limitations of each model against the scientific and therapeutic goal of a prospective preclinical study.
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http://dx.doi.org/10.15252/embj.201797397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579350PMC
September 2017

Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-β Protein Precursor Transgenic Mice.

J Alzheimers Dis 2017 ;56(2):743-761

Department of Neurology, University of Minnesota, Minneapolis, MN, USA.

There exist several dozen lines of transgenic mice that express human amyloid-β protein precursor (AβPP) with Alzheimer's disease (AD)-linked mutations. AβPP transgenic mouse lines differ in the types and amounts of Aβ that they generate and in their spatiotemporal patterns of expression of Aβ assemblies, providing a toolkit to study Aβ amyloidosis and the influence of Aβ aggregation on brain function. More complete quantitative descriptions of the types of Aβ assemblies present in transgenic mice and in humans during disease progression should add to our understanding of how Aβ toxicity in mice relates to the pathogenesis of AD. Here, we provide a direct quantitative comparison of amyloid plaque burdens and plaque sizes in four lines of AβPP transgenic mice. We measured the fraction of cortex and hippocampus occupied by dense-core plaques, visualized by staining with Thioflavin S, in mice from young adulthood through advanced age. We found that the plaque burdens among the transgenic lines varied by an order of magnitude: at 15 months of age, the oldest age studied, the median cortical plaque burden in 5XFAD mice was already ∼4.5 times that of 21-month-old Tg2576 mice and ∼15 times that of 21-24-month-old rTg9191 mice. Plaque-size distributions changed across the lifespan in a line- and region-dependent manner. We also compared the dense-core plaque burdens in the mice to those measured in a set of pathologically-confirmed AD cases from the Nun Study. Cortical plaque burdens in Tg2576, APPSwePS1ΔE9, and 5XFAD mice eventually far exceeded those measured in the human cohort.
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http://dx.doi.org/10.3233/JAD-161027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5272806PMC
February 2018

HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via β-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation.

Am J Pathol 2017 Jan;187(1):91-109

Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Mounting evidence implicates antiretroviral (ARV) drugs as potential contributors to the persistence and evolution of clinical and pathological presentation of HIV-associated neurocognitive disorders in the post-ARV era. Based on their ability to induce endoplasmic reticulum (ER) stress in various cell types, we hypothesized that ARV-mediated ER stress in the central nervous system resulted in chronic dysregulation of the unfolded protein response and altered amyloid precursor protein (APP) processing. We used in vitro and in vivo models to show that HIV protease inhibitor (PI) class ARVs induced neuronal damage and ER stress, leading to PKR-like ER kinase-dependent phosphorylation of the eukaryotic translation initiation factor 2α and enhanced translation of β-site APP cleaving enzyme-1 (BACE1). In addition, PIs induced β-amyloid production, indicative of increased BACE1-mediated APP processing, in rodent neuroglial cultures and human APP-expressing Chinese hamster ovary cells. Inhibition of BACE1 activity protected against neuronal damage. Finally, ARVs administered to mice and SIV-infected macaques resulted in neuronal damage and BACE1 up-regulation in the central nervous system. These findings implicate a subset of PIs as potential mediators of neurodegeneration in HIV-associated neurocognitive disorders.
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http://dx.doi.org/10.1016/j.ajpath.2016.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225305PMC
January 2017

BACE1 inhibition as a therapeutic strategy for Alzheimer's disease.

Authors:
Robert Vassar

J Sport Health Sci 2016 Dec 21;5(4):388-390. Epub 2016 Oct 21.

Department of Cell and Molecular Biology, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

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http://dx.doi.org/10.1016/j.jshs.2016.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188930PMC
December 2016

Identification of natural products with neuronal and metabolic benefits through autophagy induction.

Autophagy 2017 Jan 28;13(1):41-56. Epub 2016 Oct 28.

a Department of Cell and Molecular Biology , Feinberg School of Medicine, Northwestern University , Chicago , IL , USA.

Autophagy is a housekeeping lysosomal degradation pathway important for cellular survival, homeostasis and function. Various disease models have shown that upregulation of autophagy may be beneficial to combat disease pathogenesis. However, despite several recently reported small-molecule screens for synthetic autophagy inducers, natural chemicals of diverse structures and functions have not been included in the synthetic libraries, and characterization of their roles in autophagy has been lacking. To discover novel autophagy-regulating compounds and study their therapeutic mechanisms, we used analytic chemistry approaches to isolate natural phytochemicals from a reservoir of medicinal plants used in traditional remedies. From this pilot plant metabolite library, we identified several novel autophagy-inducing phytochemicals, including Rg2. Rg2 is a steroid glycoside chemical that activates autophagy in an AMPK-ULK1-dependent and MTOR-independent manner. Induction of autophagy by Rg2 enhances the clearance of protein aggregates in a cell-based model, improves cognitive behaviors in a mouse model of Alzheimer disease, and prevents high-fat diet-induced insulin resistance. Thus, we discovered a series of autophagy-inducing phytochemicals from medicinal plants, and found that one of the compounds Rg2 mediates metabolic and neurotrophic effects dependent on activation of the autophagy pathway. These findings may help explain how medicinal plants exert the therapeutic functions against metabolic diseases.
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http://dx.doi.org/10.1080/15548627.2016.1240855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240827PMC
January 2017

Astrocytes from old Alzheimer's disease mice are impaired in Aβ uptake and in neuroprotection.

Neurobiol Dis 2016 Dec 17;96:84-94. Epub 2016 Aug 17.

Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. Electronic address:

In Alzheimer's disease (AD), astrocytes undergo morphological changes ranging from atrophy to hypertrophy, but the effect of such changes at the functional level is still largely unknown. Here, we aimed to investigate whether alterations in astrocyte activity in AD are transient and depend on their microenvironment, or whether they are irreversible. We established and characterized a new protocol for the isolation of adult astrocytes and discovered that astrocytes isolated from old 5xFAD mice have higher GFAP expression than astrocytes derived from WT mice, as observed in vivo. We found high C1q levels in brain sections from old 5xFAD mice in close vicinity to amyloid plaques and astrocyte processes. Interestingly, while old 5xFAD astrocytes are impaired in uptake of soluble Aβ42, this effect was reversed upon an addition of exogenous C1q, suggesting a potential role for C1q in astrocyte-mediated Aβ clearance. Our results suggest that scavenger receptor B1 plays a role in C1q-facilitated Aβ uptake by astrocytes and that expression of scavenger receptor B1 is reduced in adult old 5xFAD astrocytes. Furthermore, old 5xFAD astrocytes show impairment in support of neuronal growth in co-culture and neurotoxicity concomitant with an elevation in IL-6 expression. Further understanding of the impact of astrocyte impairment on AD pathology may provide insights into the etiology of AD.
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http://dx.doi.org/10.1016/j.nbd.2016.08.001DOI Listing
December 2016

Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer's disease.

Neurosci Biobehav Rev 2016 Jun 1;65:326-40. Epub 2016 Apr 1.

Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address:

Over the past two decades, many studies have identified significant contributions of toxic β-amyloid peptides (Aβ) to the etiology of Alzheimer's disease (AD), which is the most common age-dependent neurodegenerative disease. AD is also recognized as a disease of synaptic failure. Aβ, generated by sequential proteolytic cleavages of amyloid precursor protein (APP) by BACE1 and γ-secretase, is one of major culprits that cause this failure. In this review, we summarize current findings on how BACE1-cleaved APP products impact learning and memory through proteins localized on glutamatergic, GABAergic, and dopaminergic synapses. Considering the broad effects of Aβ on all three types of synapses, BACE1 inhibition emerges as a practical approach for ameliorating Aβ-mediated synaptic dysfunctions. Since BACE1 inhibitory drugs are currently in clinical trials, this review also discusses potential complications arising from BACE1 inhibition. We emphasize that the benefits of BACE1 inhibitory drugs will outweigh the concerns.
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http://dx.doi.org/10.1016/j.neubiorev.2016.03.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856578PMC
June 2016

Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aβ generation in Alzheimer's disease.

Acta Neuropathol 2016 08 18;132(2):235-256. Epub 2016 Mar 18.

Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.

Alzheimer's disease (AD) is characterized by amyloid plaques composed of the β-amyloid (Aβ) peptide surrounded by swollen presynaptic dystrophic neurites consisting of dysfunctional axons and terminals that accumulate the β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) required for Aβ generation. The cellular and molecular mechanisms that govern presynaptic dystrophic neurite formation are unclear, and elucidating these processes may lead to novel AD therapeutic strategies. Previous studies suggest Aβ may disrupt microtubules, which we hypothesize have a critical role in the development of presynaptic dystrophies. To investigate this further, here we have assessed the effects of Aβ, particularly neurotoxic Aβ42, on microtubules during the formation of presynaptic dystrophic neurites in vitro and in vivo. Live-cell imaging of primary neurons revealed that exposure to Aβ42 oligomers caused varicose and beaded neurites with extensive microtubule disruption, and inhibited anterograde and retrograde trafficking. In brain sections from AD patients and the 5XFAD transgenic mouse model of amyloid pathology, dystrophic neurite halos with BACE1 elevation around amyloid plaques exhibited aberrant tubulin accumulations or voids. At the ultrastructural level, peri-plaque dystrophies were strikingly devoid of microtubules and replete with multi-lamellar vesicles resembling autophagic intermediates. Proteins of the microtubule motors, kinesin and dynein, and other neuronal proteins were aberrantly localized in peri-plaque dystrophies. Inactive pro-cathepsin D also accumulated in peri-plaque dystrophies, indicating reduced lysosomal function. Most importantly, BACE1 accumulation in peri-plaque dystrophies caused increased BACE1 cleavage of APP and Aβ generation. Our study supports the hypothesis that Aβ induces microtubule disruption in presynaptic dystrophic neurites that surround plaques, thus impairing axonal transport and leading to accumulation of BACE1 and exacerbation of amyloid pathology in AD.
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http://dx.doi.org/10.1007/s00401-016-1558-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947125PMC
August 2016

Murine versus human apolipoprotein E4: differential facilitation of and co-localization in cerebral amyloid angiopathy and amyloid plaques in APP transgenic mouse models.

Acta Neuropathol Commun 2015 Nov 10;3:70. Epub 2015 Nov 10.

Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Introduction: Amyloid β (Aβ) accumulates in the extracellular space as diffuse and neuritic plaques in Alzheimer's disease (AD). Aβ also deposits on the walls of arterioles as cerebral amyloid angiopathy (CAA) in most cases of AD and sometimes independently of AD. Apolipoprotein E (apoE) ɛ4 is associated with increases in both Aβ plaques and CAA in humans. Studies in mouse models that develop Aβ deposition have shown that murine apoE and human apoE4 have different abilities to facilitate plaque or CAA formation when studied independently. To better understand and compare the effects of murine apoE and human apoE4, we bred 5XFAD (line 7031) transgenic mice so that they expressed one copy of murine apoE and one copy of human apoE4 under the control of the normal murine apoE regulatory elements (5XFAD/apoE(m/4)).

Results: The 5XFAD/apoE(m/4) mice contained levels of parenchymal CAA that were intermediate between 5XFAD/apoE(m/m) and 5XFAD/apoE(4/4) mice. In 5XFAD/apoE(m/4) mice, we found that Aβ parenchymal plaques co-localized with much more apoE than did parenchymal CAA, suggesting differential co-aggregation of apoE with Aβ in plaques versus CAA. More importantly, within the brain parenchyma of the 5XFAD/apoE(m/4) mice, plaques contained more murine apoE, which on its own results in more pronounced and earlier plaque formation, while CAA contained more human apoE4 which on its own results in more pronounced CAA formation. We further confirmed the co-aggregation of mouse apoE with Aβ in plaques by showing a strong correlation between insoluble mouse apoE and insoluble Aβ in PS1APP-21/apoE(m/4) mice which develop plaques without CAA.

Conclusions: These studies suggest that both murine apoE and human apoE4 facilitate differential opposing effects in influencing Aβ plaques versus CAA via different co-aggregation with these two amyloid lesions and set the stage for understanding these effects at a molecular level.
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http://dx.doi.org/10.1186/s40478-015-0250-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641345PMC
November 2015

Epac2 Mediates cAMP-Dependent Potentiation of Neurotransmission in the Hippocampus.

J Neurosci 2015 Apr;35(16):6544-53

Department of Physiology and Department of Neurobiology, Northwestern University Weinberg College of Arts and Sciences, Evanston, Illinois 60208

Presynaptic terminal cAMP elevation plays a central role in plasticity at the mossy fiber-CA3 synapse of the hippocampus. Prior studies have identified protein kinase A as a downstream effector of cAMP that contributes to mossy fiber LTP (MF-LTP), but the potential contribution of Epac2, another cAMP effector expressed in the MF synapse, has not been considered. We investigated the role of Epac2 in MF-CA3 neurotransmission using Epac2(-/-) mice. The deletion of Epac2 did not cause gross alterations in hippocampal neuroanatomy or basal synaptic transmission. Synaptic facilitation during short trains was not affected by loss of Epac2 activity; however, both long-term plasticity and forskolin-mediated potentiation of MFs were impaired, demonstrating that Epac2 contributes to cAMP-dependent potentiation of transmitter release. Examination of synaptic transmission during long sustained trains of activity suggested that the readily releasable pool of vesicles is reduced in Epac2(-/-) mice. These data suggest that cAMP elevation uses an Epac2-dependent pathway to promote transmitter release, and that Epac2 is required to maintain the readily releasable pool at MF synapses in the hippocampus.
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http://dx.doi.org/10.1523/JNEUROSCI.0314-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405561PMC
April 2015

BACE1 inhibitor drugs in clinical trials for Alzheimer's disease.

Authors:
Robert Vassar

Alzheimers Res Ther 2014 24;6(9):89. Epub 2014 Dec 24.

Department of Cell and Molecular Biology, Northwestern University, The Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60611 USA.

β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the β-secretase enzyme required for the production of the neurotoxic β-amyloid (Aβ) peptide that is widely considered to have a crucial early role in the etiology of Alzheimer's disease (AD). As a result, BACE1 has emerged as a prime drug target for reducing the levels of Aβ in the AD brain, and the development of BACE1 inhibitors as therapeutic agents is being vigorously pursued. It has proven difficult for the pharmaceutical industry to design BACE1 inhibitor drugs that pass the blood-brain barrier, however this challenge has recently been met and BACE1 inhibitors are now in human clinical trials to test for safety and efficacy in AD patients and individuals with pre-symptomatic AD. Initial results suggest that some of these BACE1 inhibitor drugs are well tolerated, although others have dropped out because of toxicity and it is still too early to know whether any will be effective for the prevention or treatment of AD. Additionally, based on newly identified BACE1 substrates and phenotypes of mice that lack BACE1, concerns have emerged about potential mechanism-based side effects of BACE1 inhibitor drugs with chronic administration. It is hoped that a therapeutic window can be achieved that balances safety and efficacy. This review summarizes the current state of progress in the development of BACE1 inhibitor drugs and the evaluation of their therapeutic potential for AD.
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http://dx.doi.org/10.1186/s13195-014-0089-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304279PMC
January 2015

Aβ reduction in BACE1 heterozygous null 5XFAD mice is associated with transgenic APP level.

Mol Neurodegener 2015 Jan 7;10. Epub 2015 Jan 7.

Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60605, USA.

Background: The β-secretase, BACE1, cleaves APP to initiate generation of the β-amyloid peptide, Aβ, that comprises amyloid plaques in Alzheimer's disease (AD). Reducing BACE1 activity is an attractive therapeutic approach to AD, but complete inhibition of BACE1 could have mechanism-based side-effects as BACE1-/- mice show deficits in axon guidance, myelination, memory, and other neurological processes. Since BACE1+/- mice appear normal there is interest in determining whether 50% reduction in BACE1 is potentially effective in preventing or treating AD. APP transgenic mice heterozygous for BACE1 have decreased Aβ but the extent of reduction varies greatly from study to study. Here we assess the effects of 50% BACE1 reduction on the widely used 5XFAD mouse model of AD.

Results: 50% BACE1 reduction reduces Aβ42, plaques, and BACE1-cleaved APP fragments in female, but not in male, 5XFAD/BACE1+/- mice. 5XFAD/BACE1+/+ females have higher levels of Aβ42 and steady-state transgenic APP than males, likely caused by an estrogen response element in the transgene Thy-1 promoter. We hypothesize that higher transgenic APP level in female 5XFAD mice causes BACE1 to no longer be in excess over APP so that 50% BACE1 reduction has a significant Aβ42 lowering effect. In contrast, the lower APP level in 5XFAD males allows BACE1 to be in excess over APP even at 50% BACE1 reduction, preventing lowering of Aβ42 in 5XFAD/BACE1+/- males. We also developed and validated a dot blot assay with an Aβ42-selective antibody as an accurate and cost-effective alternative to ELISA for measuring cerebral Aβ42 levels.

Conclusions: 50% BACE1 reduction lowers Aβ42 in female 5XFAD mice only, potentially because BACE1 is not in excess over APP in 5XFAD females with higher transgene expression, while BACE1 is in excess over APP in 5XFAD males with lower transgene expression. Our results suggest that greater than 50% BACE1 inhibition might be necessary to significantly lower Aβ, given that BACE1 is likely to be in excess over APP in the human brain. Additionally, in experiments using the 5XFAD mouse model, or other Thy-1 promoter transgenic mice, equal numbers of male and female mice should be used, in order to avoid artifactual gender-related differences.
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http://dx.doi.org/10.1186/1750-1326-10-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297413PMC
January 2015