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

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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.