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Polarity determinants in endolysosomal trafficking and proteostasis: Implications for Alzheimer's disease pathogenesis

Award Number: R21AG063123
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary The vast majority of Alzheimer’s disease (AD) is sporadic, with aging being the biggest risk factor. Yet age-related changes within neurons that can drive the AD pathogenic process remain elusive. Intriguingly, there is an intricate link between the aging process and cell polarity. Dysregulation of polarity is observed in many cellular contexts during aging, such as increased permeability of epithelial barriers, defective asymmetric division of stem cells and increased frequency of cancer. However, whether brain aging and Alzheimer’s disease result from polarity dysregulation is unknown. Research in our laboratory has focused on the partitioning defective (Par) polarity proteins in neuronal development and degeneration. Interestingly, our recent studies point to a key role for Par3 in the pathogenesis of AD. AD is characterized by plaques composed of ß-amyloid (Aß), which is derived from amyloid precursor protein (APP) through cleavage by ß- and ¿-secretases. The rate-limiting step of Aß generation is the convergence between APP and its ß-secretase BACE1. We found Par3 expression is significantly reduced by middle-age, and loss of Par3 is common in human AD brains. In addition, Par3 depletion causes a significant increase in APP and BACE1 convergence. Unexpectedly, we found Aß accumulates intracellularly in the absence of Par3. Further studies suggest this is caused by defective autophagosome clearance. Remarkably, accumulation of autophagosomes and other autophagic vacuoles is also characteristic of the AD brain. Thus, these exciting data have led to our hypothesis that loss of Par3 in the aging brain promotes AD progression by targeting both APP/BACE1 convergence and autophagy. Dysregulation of these processes will lead to intracellular Aß accumulation, which is highly toxic to neurons. We will test our hypothesis through two aims. In Aim 1, we will elucidate the mechanism by which Par3 regulates APP and BACE1 convergence and intracellular Aß accumulation. In Aim 2, we will examine the mechanism by which Par3 regulates autophagy and lysosome functions. We will use a combination of BiFC, optogenetic manipulation of Par protein activity, as well as in vivo analysis in forebrain- specific Par3 conditional knockout mice. Together, our proposed studies will establish the molecular mechanisms by which Par polarity proteins are involved in AD pathogenesis. The results will shed light on the mechanism of sporadic AD in which aging is the major risk factor and polarity dysregulation may be the common feature.


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 = $0 )
2024	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Aging Research	000	2	4/4/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Aging Research	000	2	5/24/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Aging Research	000	2	12/23/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $198,750 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Aging Research	000	2	1/24/2020	NON-COMPETING CONTINUATION	$198,750
														Subtotal = $198,750

Issue Date FY: 2019 ( Subtotal = $238,500 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Aging Research	000	1	4/9/2019	NEW	$238,500
														Subtotal = $238,500

Grand Total All Awards = $437,250

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Polarity determinants in endolysosomal trafficking and proteostasis: Implications for Alzheimer's disease pathogenesis

Award Number: R21AG063123

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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