?-amyloid (A?) deposition is the main culprit in preclinical phase of Alzheimer?s disease (AD). Its rate conditions severity of ensuing neurofibrillary degeneration and precipitates the onset of cognitive deficit. Identification of AD associated variants in the TREM2 receptor, which render microglia defective in processing A? plaques, well underscores the meaning of protective function glial cell play in A? proteostasis. Like microglia, astrocytes respond to A? deposits by altering their phenotype and function, yet molecular mechanisms governing astrocytic response and those underlying the cooperative cross-talk between astrocytes and microglia in countering A? deposition remain ill-defined. In this proposal, we put forward a novel hypothesis that an astrocytic protein Peroxiredoxin (PRDX) 6 plays a pivotal role in these two intertwined processes. PRDX6 has two independent enzymatic sites endowing glutathione peroxidase (Gpx) and phospholipase 2 (PLA2) activities. PRDX6 is abundantly expressed by alveolar epithelium and endothelial cells and it is responsible for repair of peroxidatively damaged cell membrane lipids, phospholipid metabolism, and cellular signaling. In the CNS, PRDX6 is expressed by astrocytes, and its role in neurodegeneration remains unexplored. Our hypothesis is based on extensive preliminary data showing that hemizygous knock in of the overexpressing Prdx6 transgene in APP/PS1 mouse model promotes selective enticement of astrocytes to A? plaques and penetration of plaques by astrocytic processes along with increased number and phagocytic activation of periplaque microglia. This effects suppression of nascent plaque seeding and remodeling of mature plaques consequently curtailing brain A? load and A? associated neuritic degeneration. Conversely, Prdx6 haplodeficiency attenuates astro- and microglia activation around A? plaques promoting A? deposition and neuritic degeneration. Thus, our data evidence that PRDX6 expression level in astrocytes circuitously modulates microglia function implying astrocyte-guided microglia effect in A? proteostasis. Furthermore, our showing that upregulation of PRDX6 attenuates A? pathology implies a novel disease modifying strategy for AD.
Aim 1 of this application will use newly developed APP/PS1 mice, which are homozygous for the overexpressing Prdx6 transgene and APP/PS1 mice with Prdx6 knockout to determine the extent of Prdx6 overexpression expedience and conversely consequences of Prdx6 deletion on A? deposition, periplaque astro- and micro- glia response, A?-associated neurodegeneration and behavioral deficit.
Aim 2 will dissect individual effects of Gpx and PLA2 functions on curtailing A? pathology through crossing APP/PS1 mice with readily available Prdx6 mutant mice, in which selective point mutations rendered either enzymatic site inactive.
Aim 3 will employ transcriptomic approaches to identify molecular pathways involved in astro/microglia cross talk, which we expect to be altered by manipulating Prdx6 expression level in Prdx6 overexpressing and knockout mice. Transcriptomic approaches also will determine whether PRDX6 modulates activation phenotype of astrocytes and microglia and regulates glia inflammatory response.
This project investigates mechanisms underlying endowed protective effect of astrocytic protein Peroxiredoxin 6 against A? pathology, and expedience of upregulating Peroxiredoxin 6 expression as a therapeutic approach for Alzheimer?s disease. It also explores how astrocytes guide microglia to counter A? accumulation in the brain.
