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Deciphering the interactomes of ApoE and alpha-synuclein isoforms and their connections to neurodegenerative disease

Award Number: F30AG097066
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/06/2027
PERIOD OF PERFORMANCE END DATE: 02/05/2028

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Deciphering the interactomes of ApoE and alpha-synuclein isoforms and their connections to neurodegenerative disease - PROJECT SUMMARY Alzheimer's Disease (AD), Parkinson's Disease (PD), and Dementia with Lewy Bodies (DLB) are devastating neurodegenerative diseases affecting millions worldwide. Despite their distinct clinical presentations, these conditions share common genetic risk factors: apolipoprotein-E (ApoE) and alpha-synuclein (aSyn). ApoE has protective (E2, Christchurch) and risk-related (E4) isoforms, while aSyn mutations (A53T, E46K) cause early- onset aSyn aggregation and disease. Preliminary TurboID data indicate that wild-type aSyn and ApoE3 interact with 19 proteins that are significantly involved in axonal components (11 proteins), neurofilaments (4 proteins), and neurodegeneration pathways (6 proteins). This unexpected overlap suggests that both proteins influence shared axonal integrity networks essential for neuron function. The main hypothesis is that protective variants (ApoE2/Christchurch, wild-type aSyn) help maintain axonal protein networks, whereas risky variants (ApoE4, mutant aSyn) disrupt them, leading to axonal dysfunction. Importantly, axonal dysfunction is a potentially reversible process occurring early in disease development, unlike the irreversible protein clumping seen in late-stage neurodegeneration. This makes preserving axonal networks a promising therapeutic strategy that could prevent or slow disease progression across multiple disorders. Aim 1 will investigate how different variants affect axonal networks using TurboID proximity labeling to compare ApoE isoforms (E2, E3, E4, Christchurch) in astrocytes and aSyn variants (WT, A53T, E46K) in neurons in vivo. Aim 2 will evaluate clinical relevance by validating protein-protein interactions in human AD, PD, and DLB brain tissues with BAR proximity labeling and by analyzing data from neurodegenerative disease cohorts in the Global Neurodegeneration Proteomics Consortium database. This innovative approach will reveal how genetically different risk factors may converge on shared axonal pathways, potentially identifying new targets for drugs aimed at preserving neuron health across multiple neurodegenerative diseases. The goal is to develop a unifying mechanistic framework explaining how different genetic risks lead to similar clinical symptoms and overlapping pathologies. Expected outcomes include detailed, human-relevant maps of the interactome for ApoE and aSyn isoforms that clarify their roles in disease risk.


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 = $55,114 )
2026	2026	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Aging Research	000	1	8/6/2026	NEW	$55,114
														Subtotal = $55,114

Grand Total All Awards = $55,114

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Deciphering the interactomes of ApoE and alpha-synuclein isoforms and their connections to neurodegenerative disease

Award Number: F30AG097066

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/06/2027

PERIOD OF PERFORMANCE END DATE: 02/05/2028

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