# AIE, Blood-Brain Barrier Regulation, and Neurovascular Integrity in Amyloidopathy

> **NIH NIH P50** · STATE UNIVERSITY OF NY,BINGHAMTON · 2024 · $266,056

## Abstract

PROJECT SUMMARY
MAIN 3
The Blood-Brain Barrier (BBB) plays an indispensable role in protecting the Central Nervous System (CNS) by
restricting the ability of blood-borne pathogens, circulating immune cells, and macromolecules from passing into
the brain parenchyma where these agents can exert a disruptive influence on CNS function. Recent studies have
shown that BBB integrity waxes and wanes in response to psychological distress and immunological challenge,
contributing to anxiety, depression, and even heightened suicidality. Importantly, human post-mortem studies
showed BBB disruption among deceased males with Alcohol Use Disorder (AUD). Our lab recently revealed
long-lasting effects of Adolescent Intermittent Ethanol (AIE) on BBB integrity that were sex-specific and brain
region-selective. In males, AIE-induced BBB alterations were evident in early adulthood after a three-week period
of forced abstinence, whereas females were largely unaffected. These findings call for comprehensive studies
of sex-specific neurovascular dysfunction associated with AIE. One biological mechanism known to compensate
for compromised BBB integrity is through increased deposition of Amyloid-b (Ab) protein in perivascular regions,
which, as a “sticky” protein, attempts to seal the BBB and prevent enhanced permeability. Importantly, AIE has
recently been shown to increase Ab(1-42) deposition and tau hyperphosphorylation in 3X transgenic mouse model
of Alzheimer’s Disease (AD), exclusively in females when tested at 6-7 months of age. Consistent with this, we
recently reported that long-term ethanol consumption later in life increased co-localization of Ab(1-42) in iba1+
cells (microglia) that were located in close proximity to the neurovasculature exclusively in female rats, and in
the absence of transgenes that promote vulnerability to familial AD. Thus, emerging evidence suggests that
chronic intermittent ethanol exposure produces distinctive patterns of neurovascular dysfunction in males and
females, contributing to sex-specific outcomes later in life. The over-arching goal of this proposal, therefore, is
to determine the sex-specific mechanisms by which AIE produces long-lasting changes in neurovascular
integrity, with male-specific increases in BBB permeability and female-specific increases in Ab(1-42) deposition
playing major roles in AIE-associated neurovascular dysfunction. Studies proposed in three Specific Aims will (i)
fill critical gaps in our knowledge regarding natural development of the BBB during adolescence, (ii) provide new
insight into reactivity of the BBB to acute ethanol challenge during adolescence and adulthood; (iii) establish
distinct and separable paths of AIE-induced neurovascular dysfunction in male and female rats across adulthood;
and (iv) test novel hypotheses regarding loss of BBB integrity as a harbinger of neurovascular dysfunction. These
studies will provide much needed information about contributions of early life alcohol exposure to...

## Key facts

- **NIH application ID:** 10740449
- **Project number:** 2P50AA017823-16
- **Recipient organization:** STATE UNIVERSITY OF NY,BINGHAMTON
- **Principal Investigator:** Terrence Deak
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $266,056
- **Award type:** 2
- **Project period:** 2009-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10740449

## Citation

> US National Institutes of Health, RePORTER application 10740449, AIE, Blood-Brain Barrier Regulation, and Neurovascular Integrity in Amyloidopathy (2P50AA017823-16). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10740449. Licensed CC0.

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