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Selective neuronal autophagy in phosphorylated tau degradation and Alzheimer's disease

Award Number: F31AG082393
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2025
AWARD TERMINATION DATE: 08/07/2026

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Selective neuronal autophagy in phosphorylated tau degradation and Alzheimer's disease - Project Summary/Abstract: Alzheimer’s disease (AD) pathology is defined by aberrant protein aggregation of extracellular amyloid- beta plaques and intracellular hyperphosphorylated tau tangles within the brain, resulting in progressive cognitive decline. However, a plethora of amyloid-beta targeting therapies have yielded limited clinical benefit, lending credence to the significance of tau aggregation in AD. Specifically, the protein degradation network, which includes the autophagy-lysosomal system (autophagy) and the ubiquitin-proteasome system (UPS), is frequently cited as deficient in AD, and may therefore affect neurodegeneration and intracellular tau protein clearance within the brain. To investigate the mechanisms of selective protein degradation in neuronal proteostasis and AD I will use an induced pluripotent stem cell (iPSC)-derived neuronal system (iNs). Specifically, our lab has generated over 50 human iN lines from the Religious Order Study and Rush Memory and Aging Project (ROSMAP) cohorts which represent the full clinical and neuropathological spectrum of late onset AD. Across these genetically diverse iNs, we previously assayed basal autophagic flux and UPS capacity. Additionally, proteomic analysis and western blotting of these same iNs revealed strong associations between phosphorylated tau species and proteins relevant in selective autophagy of protein aggregates (aggrephagy). Of particular interest is the ubiquitin-dependent aggrephagy adaptor protein, optineurin (OPTN), which displays the most significant negative correlation with aggregated phospho-tau forms relevant in our AD neurons. BCL-2-associated athanogene 3 (BAG3) is another relevant aggrephagy chaperone protein that has previously been associated with tau homeostasis within excitatory neurons and shows a strong compensatory relationship upon UPS inhibition in our human neuronal system. Therefore, I hypothesize that AD derived neurons have a diminished capacity for protein degradation activation following exposure to AD relevant neurotoxic proteins and genetic modulation of autophagy, which results in an accumulation of phospho-tau and a reduction in neuronal activity. To address this hypothesis, I have two aims: 1) To determine the influence of OPTN regulation on neuronal tau proteostasis and neuronal function. To this end I will expose both AD and non-AD iNs to brain extract containing neurotoxic proteins and measure several forms of tau and neuronal firing. 2) To investigate the role of BAG3- mediated chaperone-assisted selective autophagy in modulating protein degradation compensation in human neurons. Here, I will modulate BAG3 expression in both AD and non-AD iNs and expose these iNs to AD brain extract containing neurotoxic proteins. I then will measure tau accumulation, neuronal firing, and protein turnover. Taken together, the findings of this proposal will not only further the understanding of tau protein degradation via aggrephagy but will define the molecular mechanisms governing OPTN and BAG3 regulation and function in neurons and may lead to novel therapeutic modalities.


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: 2026 ( Subtotal = -$11,995 )
2026	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	3	8/7/2026	TERMINATION	-$11,995
														Subtotal = -$11,995

Issue Date FY: 2025 ( Subtotal = $37,420 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	3	6/3/2025	NON-COMPETING CONTINUATION	$37,420
														Subtotal = $37,420

Issue Date FY: 2024 ( Subtotal = $42,956 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	2	5/3/2024	NON-COMPETING CONTINUATION	$42,956
														Subtotal = $42,956

Issue Date FY: 2023 ( Subtotal = $41,676 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	1	5/3/2023	NEW	$41,676
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	001	1	5/3/2023	NEW	$0
														Subtotal = $41,676

Grand Total All Awards = $110,057

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Selective neuronal autophagy in phosphorylated tau degradation and Alzheimer's disease

Award Number: F31AG082393

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2025

AWARD TERMINATION DATE: 08/07/2026

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