137 results match your criteria familial 5xfad

Benzofuranyl-2-imidazoles as imidazoline I receptor ligands for Alzheimer's disease.

Eur J Med Chem 2021 May 20;222:113540. Epub 2021 May 20.

Laboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain. Electronic address:

Recent findings unveil the pharmacological modulation of imidazoline I receptors (I-IR) as a novel strategy to face unmet medical neurodegenerative diseases. In this work, we report the chemical characterization, three-dimensional quantitative structure-activity relationship (3D-QSAR) and ADMET in silico of a family of benzofuranyl-2-imidazoles that exhibit affinity against human brain I-IR and most of them have been predicted to be brain permeable. Acute treatment in mice with 2-(2-benzofuranyl)-2-imidazole, known as LSL60101 (garsevil), showed non-warning properties in the ADMET studies and an optimal pharmacokinetic profile. Read More

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Alzheimer's disease-associated β-Amyloid does not protect against Herpes Simplex Virus 1 infection in the mouse brain.

J Biol Chem 2021 May 27:100845. Epub 2021 May 27.

Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD, 21201, United States of America; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, 21201, United States of America. Electronic address:

Alzheimer's disease (AD) is a devastating fatal neurodegenerative disease. An alternative to the amyloid cascade hypothesis is that a viral infection is key to the etiology of late-onset AD, with β-amyloid (Aβ) peptides playing a protective role. In the current study, young 5XFAD mice that overexpress mutant human amyloid precursor protein with the Swedish, Florida, and London familial AD mutations were infected with one of two strains of herpes simplex virus 1 (HSV-1), 17syn+ and McKrae, at three different doses. Read More

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Detecting Amyloid-β Accumulation via Immunofluorescent Staining in a Mouse Model of Alzheimer's Disease.

J Vis Exp 2021 04 19(170). Epub 2021 Apr 19.

Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology and NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University;

Alzheimer's disease (AD) is a neurodegenerative disease that contributes to 60-70% dementia around the world. One of the hallmarks of AD undoubtedly lies on accumulation of amyloid-β (Aβ) in the brain. Aβ is produced from the proteolytic cleavage of the beta-amyloid precursor protein (APP) by β-secretase and γ-secretase. Read More

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Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy.

Nature 2021 May 28;593(7858):255-260. Epub 2021 Apr 28.

Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA.

Alzheimer's disease (AD) is the most prevalent cause of dementia. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy. Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Read More

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A novel nutritional mixture, MBN, prevents memory impairment via inhibiting NLRP3 inflammasome formation in 5xFAD transgenic mice.

Nutr Neurosci 2021 Apr 20:1-8. Epub 2021 Apr 20.

Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, Republic of Korea.

Objectives: Amyloid beta (Aβ)-induced abnormal neuroinflammation is recognized as a major pathological factor of Alzheimer's disease (AD), which results in memory impairment. Inhibition of excessive neuroinflammation mediated by Aβ is considered a promising strategy to ameliorate AD symptoms. To regulate the inflammatory response, nutritional and dietary supplements have been used for centuries. Read More

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PIP Improves Cerebral Blood Flow in a Mouse Model of Alzheimer's Disease.

Function (Oxf) 2021 22;2(2):zqab010. Epub 2021 Feb 22.

Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT, USA.

Alzheimer's disease (AD) is a leading cause of dementia and a substantial healthcare burden. Despite this, few treatment options are available for controlling AD symptoms. Notably, neuronal activity-dependent increases in cortical cerebral blood flow (CBF; functional hyperemia) are attenuated in AD patients, but the associated pathological mechanisms are not fully understood at the molecular level. Read More

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February 2021

Acitretin reverses early functional network degradation in a mouse model of familial Alzheimer's disease.

Sci Rep 2021 Mar 23;11(1):6649. Epub 2021 Mar 23.

Focus Program Translational Neurosciences, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

Aberrant activity of local functional networks underlies memory and cognition deficits in Alzheimer's disease (AD). Hyperactivity was observed in microcircuits of mice AD-models showing plaques, and also recently in early stage AD mutants prior to amyloid deposition. However, early functional effects of AD on cortical microcircuits remain unresolved. Read More

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Maternal antibodies facilitate Amyloid-β clearance by activating Fc-receptor-Syk-mediated phagocytosis.

Commun Biol 2021 Mar 12;4(1):329. Epub 2021 Mar 12.

The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan, Israel.

Maternal antibodies (MAbs) protect against infections in immunologically-immature neonates. Maternally transferred immunity may also be harnessed to target diseases associated with endogenous protein misfolding and aggregation, such as Alzheimer's disease (AD) and AD-pathology in Down syndrome (DS). While familial early-onset AD (fEOAD) is associated with autosomal dominant mutations in the APP, PSEN1,2 genes, promoting cerebral Amyloid-β (Aβ) deposition, DS features a life-long overexpression of the APP and DYRK1A genes, leading to a cognitive decline mediated by Aβ overproduction and tau hyperphosphorylation. Read More

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Cannabidiol Ameliorates Cognitive Function via Regulation of IL-33 and TREM2 Upregulation in a Murine Model of Alzheimer's Disease.

J Alzheimers Dis 2021 ;80(3):973-977

Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, USA.

There is a dire need for due innovative therapeutic modalities to improve outcomes of AD patients. In this study, we tested whether cannabidiol (CBD) improves outcomes in a translational model of familial AD and to investigate if CBD regulates interleukin (IL)-33 and triggering receptor expressed on myeloid cells 2 (TREM2), which are associated with improved cognitive function. CBD was administered to 5xFAD mice, which recapitulate early onset, familial AD. Read More

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January 2021

DEF8 and Autophagy-Associated Genes are Altered in Mild Cognitive Impairment, Probable Alzheimer's Disease Patients and a Transgenic Model of the Disease.

J Alzheimers Dis 2021 Feb 19. Epub 2021 Feb 19.

Laboratory of Neuroprotection and Autophagy, Center for Integrative Biology, Faculty of Science, Universidad Mayor, Santiago, Chile.

Background: Disturbances in the autophagy/endolysosomal systems are proposed as early signatures of Alzheimer's disease (AD). However, few studies are available concerning autophagy gene expression in AD patients.

Objective: To explore the differential expression of classical genes involved in the autophagy pathway, among them a less characterized one, DEF8 (Differentially expressed in FDCP 8), initially considered a Rubicon family member, in peripheralblood mononuclear cells (PBMCs) from individuals with mild cognitive impairment (MCI) and probable AD (pAD) and correlate the results with the expression of DEF8 in the brain of 5xFAD mice. Read More

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February 2021

CERT reduces C16 ceramide, amyloid-β levels, and inflammation in a model of Alzheimer's disease.

Alzheimers Res Ther 2021 02 17;13(1):45. Epub 2021 Feb 17.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 50, 6229 ER, Maastricht, the Netherlands.

Background: Dysregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers which are crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains. Read More

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February 2021

Fluorescent indolizine derivative YI-13 detects amyloid-β monomers, dimers, and plaques in the brain of 5XFAD Alzheimer transgenic mouse model.

PLoS One 2020 23;15(12):e0243041. Epub 2020 Dec 23.

Department of Pharmacy and Yonsei Institute of Pharmaceutical Science, College of Pharmacy, Yonsei University, Incheon, Republic of Korea.

Alzheimer disease (AD) is a neurodegenerative disorder characterized by the aberrant production and accumulation of amyloid-β (Aβ) peptides in the brain. Accumulated Aβ in soluble oligomer and insoluble plaque forms are considered to be a pathological culprit and biomarker of the disorder. Here, we report a fluorescent universal Aβ-indicator YI-13, 5-(4-fluorobenzoyl)-7,8-dihydropyrrolo[1,2-b]isoquinolin-9(6H)-one, which detects Aβ monomers, dimers, and plaques. Read More

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January 2021

Orally Administered Benzofuran Derivative Disaggregated Aβ Plaques and Oligomers in the Brain of 5XFAD Alzheimer Transgenic Mouse.

ACS Chem Neurosci 2021 01 17;12(1):99-108. Epub 2020 Dec 17.

Pharmaceutical Sciences Division and Wisconsin Center for NanoBioSystems, University of Wisconsin, Madison, Wisconsin 53705, United States.

Amyloid-β (Aβ) aggregated forms are highly associated with the onset of Alzheimer's disease (AD). Aβ abnormally accumulates in the brain and induces neuronal damages and symptoms of AD such as cognitive impairment and memory loss. Since an antibody drug, aducanumab, reduces Aβ aggregates and delays clinical decline, clearance of accumulated Aβ in the brain is accounted as a therapeutic approach to treat AD. Read More

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January 2021

Synthetic β-hydroxy ketone derivative inhibits cholinesterases, rescues oxidative stress and ameliorates cognitive deficits in 5XFAD mice model of AD.

Mol Biol Rep 2020 Dec 19;47(12):9553-9566. Epub 2020 Nov 19.

Translational Genomics Laboratory, COMSATS University Islamabad, Park Road, Tarlai Kalan, Islamabad, 45600, Pakistan.

Alzheimer's disease (AD) is a progressive, chronic and age-related neurodegenerative disorder that affects millions of people across the world. In pursuit of new anti-AD remedies, 2-[Hydroxy-(4-nitrophenyl)methyl]-cyclopentanone (NMC), a β hydroxyl ketone derivative was studied to explore its neuroprotective potentials against AD. The in-vitro AChE and BuChE enzymes inhibition were evaluated by Ellman protocol and antioxidant potentials of NMC by DPPH free radical scavenging assay. Read More

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December 2020

Caffeoylquinic Acids in Reverse Cognitive Deficits in Male 5XFAD Alzheimer's Disease Model Mice.

Nutrients 2020 Nov 13;12(11). Epub 2020 Nov 13.

Department of Neurology, School of Medicine, Oregon Health & Science University, Portland, OR 97239, USA.

(CA) is an edible plant and a popular botanical dietary supplement. It is reputed, in Ayurveda, to mitigate age-related cognitive decline. There is a considerable body of preclinical literature supporting CA's ability to improve learning and memory. Read More

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November 2020

A novel systems biology approach to evaluate mouse models of late-onset Alzheimer's disease.

Mol Neurodegener 2020 11 10;15(1):67. Epub 2020 Nov 10.

The Jackson Laboratory, Bar Harbor, ME, 04609, USA.

Background: Late-onset Alzheimer's disease (LOAD) is the most common form of dementia worldwide. To date, animal models of Alzheimer's have focused on rare familial mutations, due to a lack of frank neuropathology from models based on common disease genes. Recent multi-cohort studies of postmortem human brain transcriptomes have identified a set of 30 gene co-expression modules associated with LOAD, providing a molecular catalog of relevant endophenotypes. Read More

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November 2020

Imbalance of Endocannabinoid/Lysophosphatidylinositol Receptors Marks the Severity of Alzheimer's Disease in a Preclinical Model: A Therapeutic Opportunity.

Biology (Basel) 2020 Nov 5;9(11). Epub 2020 Nov 5.

Instituto de Investigación Biomédica de Málaga-IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain.

Alzheimer's disease (AD) is the most common form of neurodegeneration and dementia. The endocannabinoid (ECB) system has been proposed as a novel therapeutic target to treat AD. The present study explores the expression of the ECB system, the ECB-related receptor GPR55, and cognitive functions (novel object recognition; NOR) in the 5xFAD (FAD: family Alzheimer's disease) transgenic mouse model of AD. Read More

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November 2020

Protein kinase C eta is activated in reactive astrocytes of an Alzheimer's disease mouse model: Evidence for its immunoregulatory function in primary astrocytes.

Glia 2021 Mar 17;69(3):697-714. Epub 2020 Oct 17.

The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

Alzheimer's disease (AD) is the primary cause of age-related dementia. Pathologically, AD is characterized by synaptic loss, the accumulation of β-amyloid peptides and neurofibrillary tangles, glial activation, and neuroinflammation. Whereas extensive studies focused on neurons and activation of microglia in AD, the role of astrocytes has not been well-characterized. Read More

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Peli1 impairs microglial Aβ phagocytosis through promoting C/EBPβ degradation.

PLoS Biol 2020 10 5;18(10):e3000837. Epub 2020 Oct 5.

CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.

Amyloid-β (Aβ) accumulation in the brain is a hallmark of Alzheimer's disease (AD) pathology. However, the molecular mechanism controlling microglial Aβ phagocytosis is poorly understood. Here we found that the E3 ubiquitin ligase Pellino 1 (Peli1) is induced in the microglia of AD-like five familial AD (5×FAD) mice, whose phagocytic efficiency for Aβ was then impaired, and therefore Peli1 depletion suppressed the Aβ deposition in the brains of 5×FAD mice. Read More

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October 2020

14,15-Epoxyeicosatrienoic Acid Alleviates Pathology in a Mouse Model of Alzheimer's Disease.

J Neurosci 2020 10 24;40(42):8188-8203. Epub 2020 Sep 24.

Institute of Mental Health, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, People's Republic of China

Alzheimer's disease (AD) is the leading cause of late-onset dementia, and there exists an unmet medical need for effective treatments for AD. The accumulation of neurotoxic amyloid-β (Aβ) plaques contributes to the pathophysiology of AD. encoding soluble epoxide hydrolase (sEH)-a key enzyme for epoxyeicosatrienoic acid (EET) signaling that is mainly expressed in lysosomes of astrocytes in the adult brain-is cosited at a locus associated with AD, but it is unclear whether and how it contributes to the pathophysiology of AD. Read More

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October 2020

4-Hydroxynonenal Immunoreactivity Is Increased in the Frontal Cortex of 5XFAD Transgenic Mice.

Biomedicines 2020 Sep 3;8(9). Epub 2020 Sep 3.

Department of Biological Science, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea.

Oxidative stress was implicated in the functional impairment of the frontal cortex observed in early Alzheimer's disease (AD). To elucidate this role in an animal AD model, we assessed cognitive function of 4-month-old five familial AD (5XFAD) transgenic (Tg) mice using a learning strategy-switching task requiring recruitment of the frontal cortex and measuring levels of 4-hydroxy-2--nonenal (4-HNE), a marker of oxidative stress, in their frontal cortex. Mice were sequentially trained in cued/response and place/spatial versions of the water maze task for four days each. Read More

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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.

Ronald M. Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 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. Read More

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October 2020

Multiscale causal networks identify VGF as a key regulator of Alzheimer's disease.

Nat Commun 2020 08 7;11(1):3942. Epub 2020 Aug 7.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Though discovered over 100 years ago, the molecular foundation of sporadic Alzheimer's disease (AD) remains elusive. To better characterize the complex nature of AD, we constructed multiscale causal networks on a large human AD multi-omics dataset, integrating clinical features of AD, DNA variation, and gene- and protein-expression. These probabilistic causal models enabled detection, prioritization and replication of high-confidence master regulators of AD-associated networks, including the top predicted regulator, VGF. Read More

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Alterations in odor hedonics in the 5XFAD Alzheimer's disease mouse model and the influence of sex.

Behav Neurosci 2020 Oct 6;134(5):407-416. Epub 2020 Aug 6.

Department of Pharmacology and Therapeutics, University of Florida.

Olfactory impairments, including deficits in odor detection, discrimination, recognition, and changes in odor hedonics, are reported in the early stages of Alzheimer's disease (AD). Rodent models of AD display deficits in odor learning, detection, and discrimination-recapitulating the clinical condition. However, the impact of familial AD genetic mutations on odor hedonics is unknown. Read More

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October 2020

Different effects of constitutive and induced microbiota modulation on microglia in a mouse model of Alzheimer's disease.

Acta Neuropathol Commun 2020 07 29;8(1):119. Epub 2020 Jul 29.

Institute of Neuropathology, University of Freiburg, Breisacher Str. 64, 79106, Freiburg, Germany.

It was recently revealed that gut microbiota promote amyloid-beta (Aβ) burden in mouse models of Alzheimer's disease (AD). However, the underlying mechanisms when using either germ-free (GF) housing conditions or treatments with antibiotics (ABX) remained unknown. In this study, we show that GF and ABX-treated 5x familial AD (5xFAD) mice developed attenuated hippocampal Aβ pathology and associated neuronal loss, and thereby delayed disease-related memory deficits. Read More

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Aging and Progression of Beta-Amyloid Pathology in Alzheimer's Disease Correlates with Microglial Heme-Oxygenase-1 Overexpression.

Antioxidants (Basel) 2020 Jul 21;9(7). Epub 2020 Jul 21.

Institute Teofilo Hernando for Drug Discovery, Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, 28029 Madrid, Spain.

Neuroinflammation and oxidative stress are being recognized as characteristic hallmarks in many neurodegenerative diseases, especially those that portray proteinopathy, such as Alzheimer's disease (AD). Heme-oxygenase 1 (HO-1) is an inducible enzyme with antioxidant and anti-inflammatory properties, while microglia are the immune cells in the central nervous system. To elucidate the brain expression profile of microglial HO-1 in aging and AD-progression, we have used the 5xFAD (five familial AD mutations) mouse model of AD and their littermates at different ages (four, eight, 12, and 18 months). Read More

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A Role of Low-Density Lipoprotein Receptor-Related Protein 4 (LRP4) in Astrocytic Aβ Clearance.

J Neurosci 2020 07 26;40(28):5347-5361. Epub 2020 May 26.

Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106

Amyloid-β (Aβ) deposition occurs years before cognitive symptoms appear and is considered a cause of Alzheimer's disease (AD). The imbalance of Aβ production and clearance leads to Aβ accumulation and Aβ deposition. Increasing evidence indicates an important role of astrocytes, the most abundant cell type among glial cells in the brain, in Aβ clearance. Read More

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Recognition memory impairments and amyloid-beta deposition of the retrosplenial cortex at the early stage of 5XFAD mice.

Physiol Behav 2020 08 19;222:112891. Epub 2020 May 19.

Department of Biological Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea. Electronic address:

Early diagnosis and treatment of AD are critical for delaying its progression. The present study, therefore, examined the cognitive status and neuropathological characteristics of 4-month-old 5X familial AD (5XFAD) transgenic (Tg) mice, as an early stage of AD animal model. The novel object recognition task was performed with retention tests at varying intervals (i. Read More

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Inhibitory Parvalbumin Basket Cell Activity is Selectively Reduced during Hippocampal Sharp Wave Ripples in a Mouse Model of Familial Alzheimer's Disease.

J Neurosci 2020 06 21;40(26):5116-5136. Epub 2020 May 21.

Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC 20057.

Memory disruption in mild cognitive impairment (MCI) and Alzheimer's disease (AD) is poorly understood, particularly at early stages preceding neurodegeneration. In mouse models of AD, there are disruptions to sharp wave ripples (SWRs), hippocampal population events with a critical role in memory consolidation. However, the microcircuitry underlying these disruptions is under-explored. Read More

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Paeoniflorin exerts neuroprotective effects in a transgenic mouse model of Alzheimer's disease via activation of adenosine A receptor.

Neurosci Lett 2020 06 1;730:135016. Epub 2020 May 1.

School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China. Electronic address:

Alzheimer's disease (AD) is the most common cause of dementia, characterised by advanced cognitive and memory deterioration with no effective treatments available. Previous in vitro and in vivo studies suggest that paeoniflorin (PF), a major bioactive constituent of Radix Paeoniae, might possess anti-dementia properties; however, the underlying mechanism remains unclear. The aim of the current study was to determine the therapeutic effects of PF in a transgenic mouse model of AD and to identify its mechanism. Read More

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