PATCHING AMYLOID SURFACE ONTO SOLUBLE PROTEIN - MAPPING FTD TAU AMYLOID INTERACTIONS USING A DE NOVO DESIGN…

Assistance award details

Assistance award identifier

ASST_NON_R00AG084926_075

FAIN

R00AG084926

Recipient

BRANDEIS UNIVERSITY

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$493,022

Period

Sep 1, 2024 – Aug 31, 2028

Fiscal year

2025

Place of performance state

MA

Source file

FY2025_All_Assistance_Full_20261006.zip

Description

PATCHING AMYLOID SURFACE ONTO SOLUBLE PROTEIN - MAPPING FTD TAU AMYLOID INTERACTIONS USING A DE NOVO DESIGNED SOLUBLE PROTEIN AMYLOIDS ARE HALLMARKS OF ALZHEIMER’S DISEASE (AD) AND ALZHEIMER’S DISEASE-RELATED DEMENTIAS (ADRD). IN THESE DISEASES, AMYLOIDOGENIC PROTEINS (E.G., TAU) MISFOLD AND COALESCE TO FORM INSOLUBLE DEPOSITS, WHICH APPEAR AS MICROSCOPIC LESIONS IN PATIENT BRAIN SAMPLES. WITH CRYO-EM ADVANCEMENT, THE NUMBER OF SOLVED HIGH-RESOLUTION AMYLOID STRUCTURES IS ON THE RISE. EACH AMYLOIDOGENIC PROTEIN CAN ADOPT A NUMBER OF DIFFERENT THREE-DIMENSIONAL AMYLOID STRUCTURES, EACH WITH DISTINCT MOLECULAR REPEATING STRUCTURES, WHICH IS DEFINED AS CONFORMATIONAL STRAINS. INTERESTINGLY, DISTINCT TAU CONFORMATIONAL STRAINS ARE CORRELATED TO DIFFERENT CLINICOPATHOLOGICAL PRESENTATIONS OF AD AND ADRD—STRAINS ARE HOMOGENEOUS WITHIN A DISEASE TYPE BUT VARY BETWEEN DISEASES. THERE IS CURRENTLY A LACK OF METHODS TO ARTIFICIALLY RECREATE THE AD AND ADRD PATIENT-OBSERVED CONFORMATIONAL STRAINS IN THE LAB, WHICH IS A MAJOR SETBACK FOR THE STUDY OF BIOLOGICALLY RELEVANT SPECIES AND A BARRIER TO UNDERSTANDING THE PATHOLOGICAL EFFECTS OF AMYLOIDS. THIS HIGHLIGHTS THE NEED FOR NEW METHODS TO PRESENT THE AD AND ADRD PATIENT-OBSERVED AMYLOID EPITOPES. ADDITIONALLY, AMYLOIDS ARE INHERENTLY INSOLUBLE, MAKING IT DIFFICULT TO USE TRADITIONAL DRUG SCREENING METHODS TO IDENTIFY POTENTIAL TREATMENTS, HIGHLIGHTING THE NEED TO GENERATE LARGE QUANTITIES OF SOLUBLE FORMS FOR DRUG DEVELOPMENT EFFORTS. THIS PROPOSAL AIMS TO CREATE INNOVATIVE COMPUTATIONAL TOOLS TO REBUILD TAU AMYLOID EPITOPES OBSERVED IN FRONTOTEMPORAL DEMENTIA (FTD) TAUOPATHY PATIENTS AND VALIDATE IN SITU. THE DESIGNED PROTEINS WILL THEN BE UTILIZED TO INVESTIGATE HOW THE TAU AMYLOID EPITOPES INTERACT WITH ITS BIOCHEMICAL MICROENVIRONMENT TO ELUCIDATE THEIR CAUSAL ROLE IN TAU-MEDIATED PATHOGENESIS AND TO BEGIN DEVELOPMENT OF EFFECTIVE THERAPIES FOR FTD TAUOPATHY. THE PROTEIN DESIGN CANVAS IS A Β-SOLENOID SUPERSECONDAR