# Impact of atherosclerosis, metabolic syndrome, and STAT4-dependent immunity on Alzheimer's disease

> **NIH NIH R01** · EASTERN VIRGINIA MEDICAL SCHOOL · 2021 · $402,764

## Abstract

Project Summary
The increasing evidence of cardiovascular disease-related Alzheimer’s disease (AD) progression, and the
closely associated role of inflammation in both diseases, opens new opportunities for understanding AD
mechanisms and has the potential to unveil novel avenues for therapeutic intervention. While data indicate that
atherosclerosis promotes AD development, the role of atherosclerosis-associated immunity in AD is not fully
understood. Our recent studies have revealed the role of Signal Transducer and Activator of Transcription 4
(STAT4) in critical neutrophil (N and macrophage (M functions in the context of Type 2 diabetes (T2D)-
associated atherosclerosis. These findings, in conjunction with the increasing understanding of N and M roles
in AD, suggest a novel pathway to study neuroinflammation in AD development.
In this application, we propose to investigate how STAT4 shapes N M and neuronal functions, and
thus affects neuroinflammation, long-term activity-dependent synaptic plasticity, cognitive and
behavioral functions in conditions of T2D-accelerated atherosclerosis. Aim 1 will determine how STAT4
regulates immune-associated neuroinflammation and AD-like neuropathology in T2D-associated
atherosclerosis. As we show that a high cholesterol/ high carb diet (DDC) feeding supports T2D development
and atherosclerosis in Ldlr-/- mice, we will use this model as a model of T2D-associated atherosclerosis. Stat4-/-
Ldlr-/- and Ldlr-/- mice will be fed DDC diet for 16 wks and neuroimmune cell composition, amyloid plaques
deposition, microglia activation and blood-brain barrier breakdown will be examined. To test a role of STAT4 in
neurons, irradiated 16 wk DDC fed Stat4fl/fl LysMcre/creLdlr-/- and Ldlr-/- mice transplanted with Ldlr-/- bone marrow
will be analyzed for neuroimmune composition, Aβ deposition, neuronal apoptosis, and activation of microglia.
Finally, we will test to what extent myeloid cell specific- and neuron-specific STAT4 regulates myeloid cell homing
into the AD-like brain in series of adoptive transfer experiments. In Aim 2, we will examine the extent to which
STAT4 regulates synaptic plasticity in T2D-accelerated atherosclerosis. Specifically, we will test the effect of
STAT4 deficiency on basal synaptic transmission, presynaptic transmitter release, long-term potentiation and
long-term depression of synaptic strength at Schaffer collateral-CA1 synapses, which play a critical role in
learning and long-term memory consolidation, and are impaired in AD. We will also examine whether STAT4
deficiency alters behavioral and cognitive functions in Stat4-/-Ldlr-/- and Ldlr-/- mice. Overall, this proposal will
forge new lines of investigation by identifying STAT4-dependent mechanisms by which STAT4 impacts
neuroinflammation and potential AD risk under conditions of T2D-associated atherosclerosis.

## Key facts

- **NIH application ID:** 10284431
- **Project number:** 3R01HL142129-04S1
- **Recipient organization:** EASTERN VIRGINIA MEDICAL SCHOOL
- **Principal Investigator:** Elena V Galkina
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $402,764
- **Award type:** 3
- **Project period:** 2018-04-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10284431

## Citation

> US National Institutes of Health, RePORTER application 10284431, Impact of atherosclerosis, metabolic syndrome, and STAT4-dependent immunity on Alzheimer's disease (3R01HL142129-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10284431. Licensed CC0.

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