ULTRALONG-TERM SINGLE-MOLECULE IMAGING OF AMYLOID PRECURSOR PROTEIN (APP) PROCESSING IN ALZHEIMER'S DISEASE…

Assistance award details

Assistance award identifier

ASST_NON_R00AG065516_075

FAIN

R00AG065516

Recipient

THE BROAD INSTITUTE, INC

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$722,149

Period

Dec 1, 2022 – Nov 30, 2025

Fiscal year

2023

Place of performance state

MA

Source file

FY2023_All_Assistance_Full_20261006.zip

Description

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 PURSU