# Mechanisms underlying sporadic Alzheimer's disease

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $399,750

## Abstract

ABSTRACT
More than 95% of the Alzheimer’s patients have the sporadic disease. The mechanisms
by which sporadic Alzheimer’s disease (AD) develops are not fully understood. Type 2
diabetes mellitus (T2DM) increases the risk of developing AD, suggesting a common
mechanism induced by T2DM, leading to AD. Here we show that the expression of the
endothelial protein caveolin-1 (Cav-1) is reduced in the MKR diabetic mouse model.
Cav-1 expression is progressively lost in endothelial cells as a function of disease
deterioration. We provide evidence that loss of Cav-1 is due to increased pro-
inflammatory cytokines in the MKR mice. We further show that loss of endothelial Cav-
1 compromises the expression of insulin receptor and the transport of insulin into the
brain. In addition, loss of Cav-1 results in reduced hippocampal neurogenesis,
impairments in critical neurogenic receptors and upregulation of amyloid precursor
protein (APP) in the hippocampus. These alterations are manifested by impaired
learning and memory in MKR diabetic mice. This study will test the hypothesis that
chronic inflammation associated with T2DM causes progressive endothelial Cav-1
depletion ultimately leading to AD. Aim 1 will determine the effect of Cav-1 depletion
on insulin transport and uptake in T2DM mouse models, endothelial-specific
conditional Cav-1-/- (Cdh5-CreERT2/Cav-1loxlox) and Cav-1-reconstituted MKR (EC-Cav1-
RC/MKR) transgenic mice. Aim 2 will determine the effect of Cav-1 depletion on
hippocampal plasticity and neurogenesis in T2DM mouse models. Aim 3 will examine
the effect of Cav-1 depletion on APP metabolism, the development of neuropathology
and impaired learning and memory in T2DM. Experiments will examine whether
reconstitution of Cav-1 in endothelial cells of diabetic mice (EC-Cav1-RC/MKR) will
rescue cognitive deficits and attenuate neuropathology. This study will establish a novel
mechanism underlying sporadic AD and determine the therapeutic value of intervention
in Cav-1 metabolism.

## Key facts

- **NIH application ID:** 9918826
- **Project number:** 5R01AG060238-03
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Orly Lazarov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $399,750
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918826

## Citation

> US National Institutes of Health, RePORTER application 9918826, Mechanisms underlying sporadic Alzheimer's disease (5R01AG060238-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9918826. Licensed CC0.

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