# Project 2: Molecular aspects of endocrine and metabolic dysregulation in neurodegeneration

> **NIH NIH P01** · UNIV OF ARKANSAS FOR MED SCIS · 2020 · $484,542

## Abstract

Summary – Project 2
Type-2 diabetes mellitus (T2DM) is a growing health-related concern, in part because of increases in its
incidence. However, T2DM is also significant because of emerging evidence regarding the breadth of its
effects on various body systems. It is now recognized that T2DM is associated with CNS deficits such as
dementia, including Alzheimer's disease. We have found several ways in which a gene related to Alzheimer's
influences diabetic tendencies in mice. The amyloid precursor protein (APP) serves as the source of amyloid
β-peptide (Aβ), and its mutation is capable of causing Alzheimer's. Our preliminary studies indicate that APP
exerts a powerful impact on insulin/glucose metabolism, so to test the role of Aβ itself, we have turned to mice
that over-produce this peptide alone in the CNS. These mice develop a prediabetic state (insulin resistance)
by default. We propose to determine the effects of Aβ on CNS elements that control peripheral energy
metabolism, placing particular emphasis on inflammatory processes. We also will test whether any effects of
Aβ on insulin/glucose regulation can be modulated by expression of human apolipoprotein E (ApoE). This
protein's gene (APOE) contributes the largest demographic risk to Alzheimer's disease, and ApoE both
impacts inflammation and binds Aβ in genotype-specific manners. Thus, we expect ApoE to modify the effects
that Aβ has on insulin/glucose metabolism. Finally, we will test whether the effects of Aβ on insulin/glucose
metabolism can be similarly modified by interrupting inflammation or protein aggregation; this will be
accomplished in part through cooperative strategies for drug development throughout the parent Program.
Together, these experiments will characterize the interactions between T2DM-related syndromes and proteins
of critical importance to Alzheimer's disease. The project will ultimately test pharmacological agents that
directly impact these interactions and may thus provide novel therapeutic opportunities for Alzheimer's and
T2DM.

## Key facts

- **NIH application ID:** 9964629
- **Project number:** 5P01AG012411-21
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Steven W Barger
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $484,542
- **Award type:** 5
- **Project period:** 1997-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964629

## Citation

> US National Institutes of Health, RePORTER application 9964629, Project 2: Molecular aspects of endocrine and metabolic dysregulation in neurodegeneration (5P01AG012411-21). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9964629. Licensed CC0.

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