# BDNF signaling in VMH astrocytes mediating energy and glucose balance control

> **NIH NIH R01** · TUFTS UNIVERSITY BOSTON · 2020 · $408,600

## Abstract

Project Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia.
It afflicts an evergrowing number of individuals with devastating consequences. Key features of AD pathology
are amyloid plaques holding pathological forms of Ab and neurofibrillary tangles containing hyperphosphorylated
Tau. Human association and animal studies suggest that obesity and the accompanying metabolic syndrome
are risk factors for AD. The mechanisms underlying these putative effects of metabolic dysfunction remain poorly
understood and warrant examination considering that obesity is a global health problem. Our previous studies
identified a critical role for brain-derived neurotrophic factor (BDNF) in central neural circuits controlling energy
and glucose balance. The parent grant for this administrative supplement application investigates whether
BDNF signaling through the truncated form of the TrkB receptor (TrkB.T1) in astrocytes in the ventromedial
hypothalamus (VMH) is one mechanism mediating energy balance and body weight control. The data so far
indicate that TrkB.T1 in VMH astrocytes inhibits expression of the astrocytic glutamate transporter GLT-1 and
synaptic glutamate clearance. This effect elevates the excitatory tone onto anorexigenic VMH neurons and
suppresses appetite. Moreover, we found that chronic intake of a high fat diet in normal mice elevates
expression of TrkB.T1 in hippocampus and prefrontal cortex (PFC), two brain regions involved in cognitive
function and affected in AD. These findings are relevant to AD because elevated and reduced levels of TrkB.T1
and GLT-1, respectively, have been reported in AD brain. We hypothesize that HFD-induced obesity and Ab
accumulation cooperate to increase levels of TrkB.T1 in cortical and hippocampal astrocytes. TrkB.T1, for its
part, impedes synaptic glutamate clearance and the consequent accumulation of extracellular glutamate elicits
synaptic dysfunction, exitotoxicity, neurodegeneration and ultimately, cognitive decline. To test this idea, we
propose a series of studies examining the effects of HFD consumption on TrkB.T1 in astrocytes and on glutamate
uptake kinetics in hippocampus and PFC of a mouse model of AD. Findings from these investigations will serve
as a foundation for future studies informing the relationship between obesity and the onset of AD.

## Key facts

- **NIH application ID:** 10116732
- **Project number:** 3R01DK117935-02S1
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Maribel Rios
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $408,600
- **Award type:** 3
- **Project period:** 2019-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116732

## Citation

> US National Institutes of Health, RePORTER application 10116732, BDNF signaling in VMH astrocytes mediating energy and glucose balance control (3R01DK117935-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10116732. Licensed CC0.

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