# Acceleration of AD Phenotypes in Asymptomatic Mouse Models

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2021 · $399,750

## Abstract

The aim of this study is to test the hypothesis that depletion of Caveolin-1 accelerates the Alzheimer’s
phenotype in aging and aging-linked comorbidities, such as type 2 diabetes. Caveolin-1 (Cav-1) is the principal
component of caveolae, and a critical player in lipid rafts. Cav-1 expression is reduced in aging. Here we show
that Cav-1 expression is progressively lost in the brains of two mouse models of type 2 diabetes as a function
of age and disease deterioration. Type 2 diabetes is a risk factor for Alzheimer’s disease (AD). We provide
evidence that depletion of Cav-1 in these mice results in (1) induction of amyloidogenic proteolysis of amyloid
precursor protein (APP) (2) compromised vasculature (3) impaired hippocampal neurogenesis (4) impaired
learning and memory (5) compromised transport of insulin into the brain and downregulated expression of
insulin receptor. This study will test the hypothesis that depletion of Caveolin-1 in the brain accelerates the
AD phenotype by inducing amyloidosis and compromising insulin supply into the brain, leading to cognitive
impairments. Using T2DM mouse models and Cav-1 transgenic mice Aim 1 will examine the mechanism by
which Cav-1 depletion affects APP metabolism, the development of neuropathology and impaired learning
and memory in these mice. Aim 2 will determine the effect of Cav-1 depletion on insulin transport and uptake.
Aim 3 will determine the effect of Cav-1 depletion on vasculature and hippocampal neurogenesis.
Experiments will examine whether reconstitution of Cav-1 in endothelial cells of diabetic mice will rescue
cognitive deficits and attenuate neuropathology. This study will establish the role of Cav-1 in the development
of AD and determine the therapeutic value of intervention in Cav-1 metabolism.

## Key facts

- **NIH application ID:** 10151577
- **Project number:** 5R01AG062251-04
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Orly Lazarov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $399,750
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151577

## Citation

> US National Institutes of Health, RePORTER application 10151577, Acceleration of AD Phenotypes in Asymptomatic Mouse Models (5R01AG062251-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10151577. Licensed CC0.

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