# SIRT3 Deficiency-mediated Metabolic Dysregulation in Comorbid Alzheimer's Disease

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2022 · —

## Abstract

Alzheimer's disease (AD), the most frequent cause of dementia, is characterized by accumulation of amyloid
plaques and formation of neurofibrillary tangles. Treatment of AD is a challenge because this devastating disease
often coexists with other brain lesions caused by comorbidities, including obesity, diabetes, hypertension and
cardiovascular diseases. Metabolic syndrome (MetS) is the early stage of these comorbidities and it is prevalent
among veteran population. MetS in mid-life could interact with the asymptomatic cellular phase of AD and
accelerate the disease progression. The role of comorbidities needs to be examined early because the comorbid
population may take diverse paths in terms of disease management and the type of medications used. Therefore,
epidemiological studies can sometime yield mixed findings in terms of their susceptibility to dementia. Studies of
early interactions between MetS and AD, using comorbid models of AD, can identify converging pathways.
 In MetS, mitochondrial proteins are hyperacetylated, leading to their decreased function. This protein
modification is reversed by the deacetylase enzyme, known as SIRT3, the focus of this study. SIRT3
downregulation is a critical component of MetS because (i) global knockout of Sirt3 in mice leads to
acceleration of MetS, (ii) reduced human SIRT3 activity, caused by a single point mutation (V208I), is associated
with MetS and (iii) chronic consumption of excessive calories, a cause of MetS, decreases SIRT3 levels and
activity. While SIRT3 research has generally remained in the domain of peripheral tissues, its function in brain
mitochondrial metabolism is beginning to emerge. We recently made the critical observations of
hyperacetylation/downregulation of mitochondrial proteins, impaired mitochondrial respiration, and markers of
neuroinflammation with the brain samples of Sirt3-/- mice. Therefore, we crossed these mice with Alzheimer's
transgenic (APP/PS1) mice to generate APP/PS1/Sirt3-/- mice, as a comorbid AD model with MetS. Exacerbation
of insulin resistance, amyloid pathology, neuroinflammation, microglial dysregulation and differential gene
expression patterns (RNA-seq analysis) in the brain were observed in these mice.
 Our preliminary studies suggested that SIRT3 deficiency in MetS may cause metabolic dysregulation and
neuroinflammation in midlife and accelerates cognitive decline in individuals susceptible for AD. The overall
objective of this study is to dissect the causal mechanisms by examining the roles of SIRT3 deficiency in neurons,
astrocytes and microglia of comorboid AD mouse brain. We hypothesize that “SIRT3 deficiency and amyloid
pathology interact through converging pathways of metabolic dysregulation and neuroinflammation in
comorbid AD”. This hypothesis will be tested with the following Specific Aims:
 Aim 1. To determine the effects of SIRT3 deficiency on brain mitochondrial metabolism, insulin
resistance and cognitive decline in APP/PS1/Sirt3-/- mice...

## Key facts

- **NIH application ID:** 10477264
- **Project number:** 5I01BX004480-04
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** SUBBIAH PUGAZHENTHI
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477264

## Citation

> US National Institutes of Health, RePORTER application 10477264, SIRT3 Deficiency-mediated Metabolic Dysregulation in Comorbid Alzheimer's Disease (5I01BX004480-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10477264. Licensed CC0.

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