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

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

项目成果

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SALLY ANN FRAUTSCHY其他文献

SALLY ANN FRAUTSCHY的其他文献

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{{ truncateString('SALLY ANN FRAUTSCHY', 18)}}的其他基金

Role of Complement Receptor Activation in a Mixed Dementia Model
补体受体激活在混合痴呆模型中的作用
  • 批准号:
    10585080
  • 财政年份:
    2023
  • 资助金额:
    $ 67.8万
  • 项目类别:
Metabolic and Vascular Factors in tau pathogenesis
tau 发病机制中的代谢和血管因素
  • 批准号:
    10058790
  • 财政年份:
    2020
  • 资助金额:
    $ 67.8万
  • 项目类别:
Metabolic and Vascular Factors in tau pathogenesis
tau 发病机制中的代谢和血管因素
  • 批准号:
    10414102
  • 财政年份:
    2020
  • 资助金额:
    $ 67.8万
  • 项目类别:
Metabolic and Vascular Factors in tau pathogenesis
tau 发病机制中的代谢和血管因素
  • 批准号:
    10615154
  • 财政年份:
    2020
  • 资助金额:
    $ 67.8万
  • 项目类别:
Neuroinflammation and Neurodegeneration in a Transgenic Alzheimer Rat with Vascular Disease
患有血管疾病的转基因阿尔茨海默大鼠的神经炎症和神经变性
  • 批准号:
    10478805
  • 财政年份:
    2017
  • 资助金额:
    $ 67.8万
  • 项目类别:
Modulation of tau pathogenesis by high dietary fat, gender and ApoE isoform
高膳食脂肪、性别和 ApoE 异构体对 tau 蛋白发病机制的调节
  • 批准号:
    9036260
  • 财政年份:
    2016
  • 资助金额:
    $ 67.8万
  • 项目类别:
Curcumin and Yoga Exercise Effects in Veterans at Risk for Alzheimer's Disease
姜黄素和瑜伽运动对有阿尔茨海默病风险的退伍军人的影响
  • 批准号:
    8976082
  • 财政年份:
    2013
  • 资助金额:
    $ 67.8万
  • 项目类别:
Polyphenolic Interventions for tau Pathogenesis in Alzheimers Models
多酚干预阿尔茨海默病模型中 tau 蛋白的发病机制
  • 批准号:
    8333462
  • 财政年份:
    2012
  • 资助金额:
    $ 67.8万
  • 项目类别:
Polyphenolic Interventions for tau Pathogenesis in Alzheimers Models
多酚干预阿尔茨海默病模型中 tau 蛋白的发病机制
  • 批准号:
    8597919
  • 财政年份:
    2012
  • 资助金额:
    $ 67.8万
  • 项目类别:
Curcumin and Curcumin Derivatives for Alzheimer's
姜黄素和姜黄素衍生物治疗阿尔茨海默病
  • 批准号:
    7452275
  • 财政年份:
    2006
  • 资助金额:
    $ 67.8万
  • 项目类别:

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