# Mechanisms of stress-induced neurovascular damage promoting immune infiltration and depression-like behaviors

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $423,750

## Abstract

Abstract:
Alzheimer’s Disease (AD) is a debilitating conditioned marked by accumulation of Ab and hyperphosphorylation
of tau proteins thought to lead to neurodegeneration and cognitive decline. It has been hypothesized that Ab
accumulation and tauopathy might result in damage to blood vessels that make up the blood brain barrier (BBB),
which is estimated to contribute to ~50% of all dementias worldwide, including AD. Such BBB damage is thought
to result in disease pathogenesis by increasing brain permeability and peripheral immune infiltration. Animal
models of AD-related pathology, which rely on the overexpression or knock-in of established genetic mutations,
have confirmed that the accumulation of Aβ and tau does indeed result in blood vessel abnormalities and blood-
brain barrier (BBB) breakdown (Fig 1), which is associated with behavioral symptoms including cognitive
dysfunction. In addition to cognitive decline, many AD patients also experience severe neuropsychiatric
symptoms such as depression and anxiety. While the mechanisms of comorbid neuropsychiatric symptoms with
AD are not well known, we have shown that chronic stress—a known risk factor for AD in humans—can in fact
damage the BBB. Under the parent R01MH104559, my lab has been investigating whether pro-inflammatory
cytokines such as interleukin 6 (IL-6) or immune cells themselves may diffuse more readily into the brain of
stressed mice due to vascular damage. We have found that stress reduces expression of the tight junction
protein claudin 5 (CLDN5) and leads to breakdown of the endothelial barrier allowing greater entry of IL-6 directly
into brain reward regions like the nucleus accumbens (NAc) to impair social behavior and responses to natural
rewards [15]. Interestingly, genetic mouse models of AD-related pathology confirm that they are indeed more
sensitive to the behavioral effects of stress and exhibit age-related degeneration of the BBB, which leads to
increased permeability. In this supplement we will examine the effects of chronic social stress on BBB integrity
and stress-induced behaviors in well-established mouse models of AD-related pathology.

## Key facts

- **NIH application ID:** 10121484
- **Project number:** 3R01MH104559-07S1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** SCOTT JAMES RUSSO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $423,750
- **Award type:** 3
- **Project period:** 2020-09-01 → 2020-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121484

## Citation

> US National Institutes of Health, RePORTER application 10121484, Mechanisms of stress-induced neurovascular damage promoting immune infiltration and depression-like behaviors (3R01MH104559-07S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10121484. Licensed CC0.

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