# Cerebral Vascular Smooth Muscle Dysfunction in Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $397,911

## Abstract

Abstract .
Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting millions of Americans. Despite
decades of research to understand memory and cognitive deficits and numerous clinical trials to treat the
disease, mechanisms underlying AD development and progression remain unclear and outcomes of clinical trials
uncertain. Intriguingly, an early event in AD is a decrease of cerebral blood flow (CBF) that has been associated
with oligomeric amyloid β (Aβ) accumulation and changes in the diameter of cerebral blood vessels in both
human with AD and animal models of AD. Efforts to explored whether the vasculature contributes to AD have
mainly centered on mechanisms of endothelial dysfunction. However, how vascular smooth muscle (VSM),
which contain the contractile apparatus to modulate arterial/arteriole diameter and CBF, are affected by Aβ
leading to AD development and progression are poorly understood. The overall objective of this proposal is to
address these fundamental knowledge gaps by providing a comprehensive evaluation of a link between cerebral
VSM dysfunction and Aβ accumulation/exposure. We will address the novel central hypothesis that Aβ
exposure alters VSM function and vascular reactivity by modifying the clustering and activity of the ion channel
CaV1.2, which is essential for VSM contraction. We further hypothesize that the phosphorylation state of a single
CaV1.2 amino acid - S1928 – mediates Aβ-dependent effects on CaV1.2 spatiotemporal properties. This innovative
hypotheses are formulated on the basis of strong preliminary data indicating an unanticipated and remarkable
effect of Aβ exposure in increasing S1928 phosphorylation. This was correlated with increased CaV1.2 activity and
the induction of coupled CaV1.2 events upon Aβ exposure. Increased CaV1.2 coupling results in a net
amplification of Ca2+ influx leading to enhanced vasoconstriction and altered CBF in response to Aβ, thus
underscoring the significance of this supplement. Beyond the unforeseen role for S1928 in control of arterial
CaV1.2 and vascular function in response to Aβ, an emerging and innovative concept is that pS1928 is a major
risk factor in AD. Our multiscale contemporary approach that includes innovative microscopy techniques,
sophisticated biochemistry, electrophysiology, in silico analysis and unique animal models will be implemented
to explore the following aims. Aim 1 will test the hypothesis that Aβ exposure increases CaV1.2 clustering, activity
and coupled gating. Aim 2 will test the hypothesis that pS1928 is essential for Aβ-induced CaV1.2 clustering and
coupled gating. The impact of the application lies in uncovering fundamental new mechanistic insight of a link
between cerebral VSM dysfunction and AD that could be exploited for the rational development of treatment
strategies that reduce the risk of vascular and neuronal complications.

## Key facts

- **NIH application ID:** 10488479
- **Project number:** 3R01HL149127-04S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Manuel F Navedo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $397,911
- **Award type:** 3
- **Project period:** 2019-06-10 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10488479

## Citation

> US National Institutes of Health, RePORTER application 10488479, Cerebral Vascular Smooth Muscle Dysfunction in Alzheimer's Disease (3R01HL149127-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10488479. Licensed CC0.

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