# Role of Adaptive Immunity in Etiology of Alzheimer’s Disease andAlzheimer’s Disease-Related Dementias

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $829,615

## Abstract

Technical Abstract
 It is now appreciated that the adaptive immune system plays an integral role in the removal of toxic Aβ
oligomers from Alzheimer disease (AD) brains. This is accomplished through T effector cell entry into the brain
via the choroid plexus (CP) and their subsequent interaction with resident microglia. However, the role of the T
regulatory (Tregs) cells, which moderate Teff antigen inflammatory response, in the removal of Aβ oligomers is
currently debated. We have found that Treg cells are oxidative while Teff cells are glycolytic and that AD is
associated with chronic mitochondrial oxidative phosphorylation (OXPHS) defects and increased mitochondrial
reactive oxygen species (mROS) production. Therefore, we hypothesize that preexisting differences in
mitochondrial OXPHOS and mROS production can predispose to Alzheimer disease amyloid
accumulation and cognitive decline due to chronic neuronal cell damage, stimulation of toxic Aβ
oligomer formation, and alteration in the Treg control of immune function.
 To test this hypothesis, we propose three specific aims. First, to determine the importance of
mitochondrial defects in AD, we will combine the classical nuclear DNA (nDNA) APPswe AD transgene with
mtDNAs harboring defined OXPHOS defects (COIV421A and ND6P25L) or established Treg suppressive function
(mtDNAB6 and mtDNANZB) and document their effects on clearance of Aβ plaques and restoration of cognitive
function. Second, to determine the role of Treg in modulating Aβ pathology and cognition, we will use adoptive
transfer of weakly Teff-suppressive mtDNANZB Treg cells and strongly Teff-suppressive mtDNAB6 Treg cells in
APPswe mtDNAB6 or mtDNANZB mice and evaluate Aβ plaque removal and cognitive function. Lastly, to
determine the effects of mitochondrial OXPHOS defects and mROS production on the central nervous system,
CP, Treg cells, and microglia in terms of Aβ pathology and cognitive decline, we will use tissue-specific Cre
recombinases to either 1) inactivate the nuclear Ant2fl gene thereby reducing OXPHOS or 2) activate the
mitochondrially-targeted anti-oxidant mCATfl gene, thereby reducing mROS in Tg2576 APPswe + mtDNAB6 or
mtDNANZB mice.
 According to our hypothesis, the first specific aim is predicted to confirm that mitochondrial dysfunction
is causally related to AD and that mitochondria modulate the anti-Aβ oligomer removal by Treg cells. The
second specific aim is predicted to confirm the importance of Treg mitochondrial function in Aβ plaque
removal. The last specific aim is predicted to confirm the role of partial OXPHOS defects in the brain and
microglia in predisposition to AD and to establish the importance of Treg mROS in modulating Aβ plaque
removal and cognitive pathology. Should these predictions be born out, they may suggest that therapies to
enhance mitochondrial function and reduce mROS may prove beneficial in treating AD.

## Key facts

- **NIH application ID:** 10841646
- **Project number:** 5R01AG078814-03
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Douglas C Wallace
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $829,615
- **Award type:** 5
- **Project period:** 2022-09-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841646

## Citation

> US National Institutes of Health, RePORTER application 10841646, Role of Adaptive Immunity in Etiology of Alzheimer’s Disease andAlzheimer’s Disease-Related Dementias (5R01AG078814-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10841646. Licensed CC0.

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