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Metabolic and Vascular Factors in tau pathogenesis

tau 发病机制中的代谢和血管因素

基本信息

批准号：
10261582
负责人：
SALLY ANN FRAUTSCHY
金额：
$ 67.8万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10261582
关键词：
3xTg-AD mouse APP-PS1 Acceleration Address Adverse effects Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Amyloid Amyloid beta-Protein Angiotensin II Receptor Antihypertensive Agents Apolipoprotein E Attenuated Behavior Behavioral Biochemical Biological Markers Blood Plasma Volume Blood Pressure Blood Vessels Brain Breeding Cerebrospinal Fluid Cerebrovascular Disorders Cilostazol Clinic Cognitive Combined Modality Therapy Complex Consensus Data Dementia Demyelinations Diagnostic Drops Endothelial Cells Endothelium Estrogen Antagonists Estrogen Receptors Estrogens Exhibits Experimental Designs Extravasation FDA approved Female Genetic Glial Fibrillary Acidic Protein Goals Human Hypertension Inbred WKY Rats Individual Inflammation Intervention Knowledge Longitudinal Studies Losartan Menopause Metabolic Methods Microglia Microvascular Dysfunction Mitochondria Modeling Mus Nerve Degeneration Neuroglia Neuropil Neuropsychology Oral Pathogenesis Pathologic Pathology Pathway interactions Pericytes Pharmaceutical Preparations Phenotype Plasma Polypharmacy Population Postmenopause Pre-Clinical Model Publishing RNA Rat Strains Rattus Research Priority Risk Risk Factors Rodent Severities Signal Transduction Stroke Study models Surrogate Markers Tauopathies Testing Therapeutic Transgenes Validation Vascular Cognitive Impairment Vascular Diseases Vascular Endothelial Growth Factors Woman apolipoprotein E-3 apolipoprotein E-4 base behavioral phenotyping blood pressure regulation cell type cerebrovascular cohort comorbidity dementia risk drug efficacy epidemiology study exosome experience high salt diet human female improved inhibitor/antagonist male men mixed dementia mutant neuroimaging neuroinflammation neuropsychiatry neurovascular injury neurovascular unit normotensive novel protective effect screening sex spatial memory synergism tau Proteins tool transcriptome sequencing vascular factor vascular inflammation β-amyloid burden

项目摘要

ABSTRACT This revised proposal utilizes our recently described novel model of Mixed Dementia (MxD) (Denver et al. 2019), the most prevalent dementia, yet MxD subjects are often excluded from AD trials. There is a paucity of models with coexisting vascular and Alzheimer's (AD) pathologies, in addition to a lack of consensus in neuropathological (or neuropsychiatric) diagnostic criteria for MxD. Therefore, this proposal seeks to identify synergistic and independent interactions between AD and hypertension-associated cerebrovascular disease factors in pathology, behavior and biomarkers and modulation by treatment, sex and ApoE isotype. The SHR- Stroke prone (SHRSP) rat is the most widely studied model for vascular cognitive impairment (VCI) and develop vascular pathology and a compromised neurovascular unit. We used this to create “SHRSPFAD” rats by breeding in mutant APP/PS1 transgenes. Our SHRSPFAD rat shows multiple features of MxD including tauopathy, recently speculated to be increased disproportionately to amyloid in MxD. We propose four aims, which include methods to address limitations of one of the controls: normotensive WKY rats (founder of SHRSP), which is used as the non-hypertensive control, but poses the same limitations as AD models with homozygous colonies (e.g. ApoETR, 3xTg mice etc.), so the aims attempt to overcome this limitations, such as exploring how severity of hypertension affects the synergism between AD and hypertension within phenotype. Aim 1 determines if further increasing hypertension, using high salt diet, used with SHSRP to exacerbate hypertension (and lower VEGF and VGF) affects aging or sex modulation of synergism between AD and hypertension. Aim 2 also addresses this limitation, by reducing hypertension with Angiotensin II Receptor Blockers (ARBs), known to protect the BBB and reduce dementia risk. Thus Aim 2 validates hypertensive-dependent effects on pathology, biomarkers and behavior using ARBs in the SHRSPFAD model. Aims 3 and 4 address effects of ApoE4 the main genetic AD risk factor (notably in women), also impactsing vasculature. Hypertension in post- menopausal female E4 carriers creates a high dementia risk unlike rodents that lack a precipitous drop in antihypertensive and neuroprotective estrogen. Therefore Aim 3: characterizes a novel ApoE SHRSPFAD model and determines the impact of losartan and the anti-estrogen receptors involved in BP control. Since comorbidities in MxD introduce multiple pathways, polypharmacy is necessary in the clinic. Disruption of VEGF signaling is seen in VCI and with ApoE4, so we evaluate the effects of ARB with the FDA approved PPD3 inhibitor Cilostazol, which restores VEGF signaling, protecting the neurovascular unit. Thus, Aim 4 determines efficacy of the combination therapy ARB and Cilostazol. Aims 1-4 variables: vascular- dependent and cognitive variables, bulk and glia- and endothelial-specific RNAseq analysis, tau, Aβ, demyelination, mitochondrial deficits and brain- derived exosomal plasma biomarkers associated with neuroinflammation and disruption of the perivascular unit.

摘要