Microhemorrhages and vasogenic edema are pathological phenomena that occur in both cerebrovascular disease (CBVD) and Alzheimer's disease (AD). In CBVD these can occur throughout the brain, yet are most frequently subcortical. In AD they usually occur at sites of vascular amyloid deposition. Given that CBVD and AD are not always mutually exclusive but often co-exist it is important that we understand the mechanisms of microhemorrhages and vasogenic edema. We hypothesize that inflammatory-mediated activation of matrix metalloproteinases leads to degeneration of tight junction proteins and basement membrane proteins resulting in vascular leakage producing microhemorrhages and/or vasogenic edema. Our goal for this proposal is to model CBVD in mouse models of amyloid deposition to produce vasogenic edema and microhemorrhage and determine the role of the MMP system in their onset and the impact CBVD has on response to amyloid-targeted therapies. We will assess inflammatory changes and activation of the MMP systems as mechanisms for these abnormalities. Importantly, we propose to acquire MR FLAIR and Susceptibility Weighted (SWI) images to assess vasogenic edema and microhemorrhage as well as any other brain changes occurring through the course of the studies. Immediately prior to tissue harvest we will acquire arteral spin label (ASL) scans to measure brain perfusion and thus enable a comparison of the density of microhemorrhages and brain health. Additionally, we will acquire contrast enhanced T1-weighted scans following administration of Magnevist and Galbumin contrast agents to assess vascular leakage. We propose to use AAV and pharmacological agents to inhibit MMPs directly, or inhibit the inflammatory signals thought to be increasing MMP activity. We will also examine whether the efficacy and side-effect profile of two A?- targeted therapies in trials are influenced by the presence of CBVD in amyloid-depositing mice. The overall goal of our proposal is to determine the time-course of CBVD pathology when we generate CBVD in APP/PS1 transgenic mice, determine the roles of inflammation and MMPs in the generation of microhemorrhage and vasogenic edema, and finally to establish the effect CBVD has on the response to A?-targeted therapies. We believe that CBVD is common co- morbidity with AD that influences the pathogenesis of AD and response to therapy.
Cerebrovascular disease commonly occurs with aging, as does Alzheimer's disease. In fact, it is estimated that 40% of Alzheimer's patients also have cerebrovascular disease. Our research proposal will examine the impact cerebrovascular disease has on the progression of amyloid pathology, a brain pathology in Alzheimer's disease. Our overall goal is to enhance our understanding of the relationship between cerebrovascular disease and Alzheimer's disease and how one can affect the other.
|Weekman, Erica M; Sudduth, Tiffany L; Caverly, Carly N et al. (2016) Reduced Efficacy of Anti-A? Immunotherapy in a Mouse Model of Amyloid Deposition and Vascular Cognitive Impairment Comorbidity. J Neurosci 36:9896-907|
|Weekman, Erica M; Wilcock, Donna M (2016) Matrix Metalloproteinase in Blood-Brain Barrier Breakdown in Dementia. J Alzheimers Dis 49:893-903|
|Head, Elizabeth; Lott, Ira T; Wilcock, Donna M et al. (2016) Aging in Down Syndrome and the Development of Alzheimer's Disease Neuropathology. Curr Alzheimer Res 13:18-29|
|Van Eldik, Linda J; Carrillo, Maria C; Cole, Patricia E et al. (2016) The roles of inflammation and immune mechanisms in Alzheimer's disease. Alzheimers Dement (N Y) 2:99-109|
|Hainsworth, Atticus H; Yeo, Natalie E; Weekman, Erica M et al. (2016) Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID). Biochim Biophys Acta 1862:1008-17|
|Madigan, Jeremy B; Wilcock, Donna M; Hainsworth, Atticus H (2016) Vascular Contributions to Cognitive Impairment and Dementia: Topical Review of Animal Models. Stroke 47:1953-9|
|Latta, Clare H; Sudduth, Tiffany L; Weekman, Erica M et al. (2015) Determining the role of IL-4 induced neuroinflammation in microglial activity and amyloid-? using BV2 microglial cells and APP/PS1 transgenic mice. J Neuroinflammation 12:41|
|Snyder, Heather M; Corriveau, Roderick A; Craft, Suzanne et al. (2015) Vascular contributions to cognitive impairment and dementia including Alzheimer's disease. Alzheimers Dement 11:710-7|
|Latta, C H; Brothers, H M; Wilcock, D M (2015) Neuroinflammation in Alzheimer's disease; A source of heterogeneity and target for personalized therapy. Neuroscience 302:103-11|
|Sudduth, Tiffany L; Weekman, Erica M; Brothers, Holly M et al. (2014) ?-amyloid deposition is shifted to the vasculature and memory impairment is exacerbated when hyperhomocysteinemia is induced in APP/PS1 transgenic mice. Alzheimers Res Ther 6:32|
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