# Mechanisms of cognitive impairment caused by atherosclerosis and red blood cell released ATP

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2024 · $835,288

## Abstract

Project Summary
With a fast pace of population aging, the prevalence of cognitive impairment and dementia including Alzheimer’s
disease is expected to rise exponentially, placing an enormous social and economic burden worldwide.
Epidemiologic and pathological studies have indicated an association between vascular diseases and cognitive
dysfunction, implicating vascular contributions to cognitive impairment and dementia (VCID). However, the
driving pathologic mechanisms of VCID remain unclear, preventing the development of effective prevention and
treatments. In response to the NIH Notice of Special Interest (NOT-HL-23-002): Promoting research to
understand VCID, this proposal aims to identify the mechanisms of cognitive impairment caused by
atherosclerosis and red blood cell (RBC) released ATP using both animal models and human samples.
Atherosclerosis is the leading cause of vascular disease worldwide, yet the role of atherosclerosis in cognitive
impairment and the underlying mechanisms remain largely unknown. Our study using high fat diet (HFD)-fed
ApoE-/- mice showed that atherosclerotic plaques extensively blocked carotid and intracranial arteries, resulting
in brain hypoperfusion, cerebrovascular remodeling and neuroinflammation. Importantly, cognitive behavior tests
detected significant memory deficits in ApoE-/- mice as early as 12 weeks with HFD, but not in age matched mice
with normal diet, demonstrating a causal relationship between atherosclerosis and cognitive impairment. Our
study also showed that disturbed blood flow-triggered ATP release from RBCs via pannexin 1 channel (Panx1)
contributes significantly to the initiation and progression of atherosclerosis as well as cognitive impairment.
Specifically, Panx1 deletion from RBCs led to reductions of plaque formation and alleviations of the cognitive
deficit in HFD-fed ApoE-/- mice. Additionally, we showed that hypercholesterolemia enhances vascular
endothelial cell (EC) [Ca2+]i responses to ATP, a key signaling for EC barrier dysfunction. These findings led to
our central hypothesis that atherosclerosis-induced brain hypoperfusion and vascular inflammation via
hypercholesterolemia along with RBC-released ATP are the key risk factors of atherosclerosis-driven cognitive
impairment. Three specific hypotheses will be tested experimentally in vivo, in vitro, and computationally in silico
under three specific aims. Aim 1: The atherosclerotic blockage of carotid and intracranial arteries causes brain
hypoperfusion and cerebrovascular remodeling, resulting in cognitive impairment. Aim 2: RBC-released ATP
contributes significantly to atherosclerosis-induced cerebrovascular pathology as well as the onset and
progression of cognitive impairment. Aim 3: Hypercholesterolemia and hemodynamic alteration-induced RBC
released ATP are the key risk factors synergistically contribute to atherosclerosis induced cerebrovascular
inflammation and EC barrier dysfunction in mice and humans. The new knowledge g...

## Key facts

- **NIH application ID:** 10945013
- **Project number:** 1R01NS139128-01
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Prosenjit Bagchi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $835,288
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10945013

## Citation

> US National Institutes of Health, RePORTER application 10945013, Mechanisms of cognitive impairment caused by atherosclerosis and red blood cell released ATP (1R01NS139128-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10945013. Licensed CC0.

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