# Rescuing neurovascular coupling to protect neuronal plasticity and cognition

> **NIH NIH RF1** · UNIVERSITY OF COLORADO DENVER · 2022 · $1,806,527

## Abstract

Summary
Growing evidence points towards the contribution of altered brain microcirculation to cognitive impairment and
dementia observed in Alzheimer’s disease (AD) and AD-related dementia (ADRD). Yet, the lack of approaches
to image the small cerebrovasculature and investigate its function has hampered our progress in understanding
the pathological sequence of vascular cognitive impairment and dementia (VCID). The earliest signs of AD and
VCID in patients and mouse models typically involve deficits in spatial and short-term memory—cognitive
functions that are critically sustained by synaptic plasticity in the hippocampus. Neurons have limited energy
reserves and thus rely on a “just-in-time” neurovascular coupling (NVC) strategy in which active regions signal
to the microvasculature to locally dilate and increase local blood flow. Patients and mouse models of AD or
CADASIL, a monogenic archetypal form of VCID, show an early deterioration in NVC. Our previous studies have
identified a molecular defect at play in capillary endothelial cells and developed a therapeutic approach that
acutely restores NVC in the mouse model of AD and CADASIL. Specifically, we found that systemic injection of
phospholipid PIP2 is sufficient to rescue neurovascular deficits by enabling Kir2.1 channels to act as sensors of
increases in external K+—a product of neuronal activity—and transduce this into a vasodilator electrical signal
that rapidly propagates to upstream arterioles, driving vasodilation to produce local hyperemia. Our
multidisciplinary team, with complementary expertise in cutting-edge imaging of brain microcirculation and
synaptic plasticity underlying learning and memory processes, will test the hypothesis that NVC restoration will
mitigate the synaptic plasticity deterioration in the hippocampus, and its behavioral consequences, observed in
AD. We further propose to investigate and compare these functions in CADASIL, a vascular driven form of ADRD.
To attain this goal, we will advance our PIP2-based strategy to chronically restore NVC in AD and CADASIL
models, and assess the treatment efficiency by developing innovative imaging approaches ex vivo, with a novel
intact capillary-arteriolar (CaPA) preparation established by our group, and in vivo using implanted graded-index
(GRIN) lenses combined with 2-photon microscopy to investigate NVC in the hippocampus. Ultimately, we will
measure the effect of NVC rescue on hippocampal synaptic plasticity deterioration caused by AD and CADASIL
conditions, and use contextual fear conditioning as a behavioral readout. Completing this study will help elucidate
the mechanisms linking NVC dysfunction to dementia in AD/ADRDs, and NVC restoration as a potential therapy.
The proposed work has the potential to provide a paradigm-shifting view on how brain microcirculation sustains
learning and memory processes.

## Key facts

- **NIH application ID:** 10530887
- **Project number:** 1RF1NS129022-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** MARK L DELL'ACQUA
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,806,527
- **Award type:** 1
- **Project period:** 2022-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10530887

## Citation

> US National Institutes of Health, RePORTER application 10530887, Rescuing neurovascular coupling to protect neuronal plasticity and cognition (1RF1NS129022-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10530887. Licensed CC0.

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