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Ultralong-term single-molecule imaging of amyloid precursor protein (APP) processing in Alzheimer's disease

Award Number: R00AG065516
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Ultralong-term single-molecule imaging of amyloid precursor protein (APP) processing in Alzheimer's disease - PROJECT SUMMARY/ABSTRACT Cleavage of amyloid precursor protein (APP) by b-site APP cleaving enzyme-1 (BACE-1) is the rate- limiting step in production of Ab, whose deposition is the pathological hallmark of Alzheimer’s disease (AD). Despite a rapidly growing burden of health care for the aging United States, there is a fundamental gap in understanding how trafficking and mutations of APP influence neuronal function and contribute to AD pathogenesis. Continued existence of this gap represents a critical problem because, until it is filled, AD prevention and treatment based on molecular understanding of the disease progression remains inaccessible. Since neurons can grow axons that are up to a meter long, continuous imaging of APP trafficking and processing in live neurons at the single-molecule level requires extremely photostable fluorophores. Our lab has recently developed a new class of upconversion nanoparticles (UCNPs) that are immensely photostable over months. The overall objective of this project is to use our novel photostable UCNPs to perform single-molecule imaging of the trafficking and processing of APP in live human induced neurons (iNs) – an excellent model system as many human diseases are not fully recapitulated in mouse neurons. The central hypothesis is that mutations of APP lead to impaired axonal transport and render APP more vulnerable for b-cleavage by BACE-1. This hypothesis has been formulated on the basis of previous work on culture mouse neurons and transgenic mouse models. The rationale for the proposed research is that ultralong-term single molecule imaging of WT and mutant APP in human iNs will reveal axonal transport defects caused by AD-associated mutations, providing important insights into their relationship to AD. Guided by strong preliminary data on the novel experimental platform, the hypothesis will be tested by pursuing the three specific aims: 1) Measure the trafficking dynamics of endocytosed APP in human iNs; 2) Determine how axonal transport is impaired by mutations of APP in human iNs; and 3) Visualize the association dynamics of APP and BACE-1 in human iNs. A battery of techniques including single-molecule imaging, nanotechnology, biochemistry and stem cell technology will be used to interrogate APP trafficking. The approach is innovative because it departs from the status quo by utilizing extremely photostable UCNPs to perform long-term single- molecule tracking, novel analysis for non-invasive determination of motor number, and the use of human induced neurons. The proposed research is significant because it is expected to characterize in depth the trafficking and association dynamics of APP and BACE-1 with unprecedented spatiotemporal resolution, as well as uncover the extent to which APP mutations impair axonal transport, thereby shedding light on future prevention and treatment of AD.


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: 2025 ( Subtotal = $211,504 )
2025	2025	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Aging Research	000	5	11/27/2024	NON-COMPETING CONTINUATION	$211,504
														Subtotal = $211,504

Issue Date FY: 2024 ( Subtotal = $243,728 )
2024	2024	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Aging Research	001	4	5/13/2024	NON-COMPETING CONTINUATION	$24,372
2024	2024	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Aging Research	000	4	11/15/2023	NON-COMPETING CONTINUATION	$219,356
														Subtotal = $243,728

Issue Date FY: 2023 ( Subtotal = $248,363 )
2023	2023	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Aging Research	001	3	12/14/2022	EXTENSION WITH OR WITHOUT FUNDS	$0
2023	2023	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Aging Research	000	3	11/30/2022	EXTENSION WITH OR WITHOUT FUNDS	$248,363
														Subtotal = $248,363

Grand Total All Awards = $703,595

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Ultralong-term single-molecule imaging of amyloid precursor protein (APP) processing in Alzheimer's disease

Award Number: R00AG065516

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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