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Mechanisms of Peroxiredoxin 6 Endowed Protection in Alzheimer’s Disease

Award Number: R01AG067478
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Mechanisms of Peroxiredoxin 6 Endowed Protection in Alzheimer’s Disease - Project Summary β-amyloid (Aβ) 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 Aβ plaques, well underscores the meaning of protective function glial cell play in Aβ proteostasis. Like microglia, astrocytes respond to Aβ 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 Aβ 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 Aβ 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 Aβ load and Aβ associated neuritic degeneration. Conversely, Prdx6 haplodeficiency attenuates astro- and microglia activation around Aβ plaques promoting Aβ deposition and neuritic degeneration. Thus, our data evidence that PRDX6 expression level in astrocytes circuitously modulates microglia function implying astrocyte-guided microglia effect in Aβ proteostasis. Furthermore, our showing that upregulation of PRDX6 attenuates Aβ 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 Aβ deposition, periplaque astro- and micro- glia response, Aβ-associated neurodegeneration and behavioral deficit. Aim 2 will dissect individual effects of Gpx and PLA2 functions on curtailing Aβ 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $423,750 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	000	5	1/9/2024	NON-COMPETING CONTINUATION	$381,375
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	001	5	6/10/2024	NON-COMPETING CONTINUATION	$42,375
														Subtotal = $423,750

Issue Date FY: 2023 ( Subtotal = $423,750 )
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	000	4	2/1/2023	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2022 ( Subtotal = $423,750 )
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	000	3	1/17/2022	NON-COMPETING CONTINUATION	$381,375
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	001	3	5/10/2022	NON-COMPETING CONTINUATION	$42,375
														Subtotal = $423,750

Issue Date FY: 2021 ( Subtotal = $423,750 )
2021	2021	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	000	2	2/5/2021	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2020 ( Subtotal = $423,750 )
2020	2020	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	000	1	4/27/2020	NEW	$423,750
														Subtotal = $423,750

Grand Total All Awards = $2,118,750

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Mechanisms of Peroxiredoxin 6 Endowed Protection in Alzheimer’s Disease

Award Number: R01AG067478

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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