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

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $691,234

## Abstract

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.

## Key facts

- **NIH application ID:** 10864941
- **Project number:** 5R01AG074552-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Daniel A Lawrence
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $691,234
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10864941

## Citation

> US National Institutes of Health, RePORTER application 10864941, The Role of PAI-1 in Cerebral Microvascular Dysfunction and the Development of Alzheimer’s Disease Neuropathology (5R01AG074552-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10864941. Licensed CC0.

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