The Role of PAI-1 in Cerebral Microvascular Dysfunction and the Development of Alzheimer’s Disease Neuropathology

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ABSTRACT The pathophysiology of Alzheimer’s disease (AD) is complex and represents one of the most difficult and pressing challenges facing modern neuroscience. Intracellular neurofibrillary tangles (NFTs) comprised of hyperphosphorylated tau and senile plaques consisting of aggregated extracellular amyloid beta (Aβ) are the hallmark pathological features of AD. However, it is clear that other factors likely contribute to the neural system failure and cognitive impairments associated with AD. Mounting clinical and experimental data suggest that cardiovascular disease (CVD) risk factors that promote vascular remodeling and dysfunction are associated with cognitive impairment, and are significant risk factors for the development of AD dementia. These studies include observations directly linking pathways associated with vascular injury such as hemostasis, angiogenesis, and hypertension to AD, leading to the hypothesis that CVD risk factors may act via common mechanisms to promote AD development or progression. For example, current data show that plaques, tangles, and CVD risk factors all upregulate expression of plasminogen activator inhibitor 1 (PAI-1), an independent CVD risk factor. Recent studies also suggest that PAI-1 may be a diagnostic biomarker and/or a risk factor for clinical AD, and PAI-1 expression increases with age, the most significant risk factor for AD dementia. PAI-1 is best understood for its role regulating fibrinolysis and wound, and in mouse models of AD PAI-1 deficiency is correlated with improved outcomes. In preliminary data presented here in the 5XFAD amyloidogenic mouse model we find that significant vascular remodeling occurs concurrently with amyloid plaque development and cognitive impairment. These changes are associated with reductions in cortical blood flow and increased PAI-1 expression. RNA-Seq and pathway analysis identify highly significant increases in gene expression in pathways known to be involved in vascular remodeling in the 5XFAD mice compared to Wt littermates, including pathways associated with angiogenesis and cardiovascular development. We also find that pharmacologic inhibition of PAI-1 in 5XFAD mice reduces abnormal vascular remodeling and improves cognition in the 5XFAD mice, without reducing plaque burden; and importantly that expression of genes within the vascular remodeling pathways are dramatically reduced in 5XFAD mice receiving the PAI-1 inhibitor. Based on the current literature and our preliminary data we will test the novel hypothesis that there is a causal relationship between vascular remodeling, and impaired cognition in the context AD, and that PAI-1 plays a critical role promoting pathologic vascular remodeling during AD development and progression.