MECHANISMS AND CONSEQUENCES OF TAU INTERNALIZATION AND AGGREGATION IN THE CENTRAL NERVOUS SYSTEM - THE AGGR…

Assistance award details

Assistance award identifier

ASST_NON_R00AG064116_075

FAIN

R00AG064116

Recipient

UNIVERSITY OF MASSACHUSETTS

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$856,880

Period

Feb 1, 2021 – May 31, 2024

Fiscal year

2021

Place of performance state

MA

Source file

FY2021_All_Assistance_Full_20261006.zip

Description

MECHANISMS AND CONSEQUENCES OF TAU INTERNALIZATION AND AGGREGATION IN THE CENTRAL NERVOUS SYSTEM - THE AGGREGATION OF THE PROTEIN TAU OCCURS IN A RANGE OF NEURODEGENERATIVE DISEASES, INCLUDING ALZHEIMER’S DISEASE1. THE PRESENCE OF TAU AGGREGATES, ALSO KNOWN AS NEUROFIBRILLARY TANGLES (NFTS), IS CORRELATED WITH DISEASE SYMPTOMS AND CLINICAL SEVERITY IN PATIENTS2. IN ADDITION TO TAU PATHOLOGY, THE ABILITY OF INNATE IMMUNE CELLS IN THE BRAIN, PARTICULARLY MICROGLIA AND ASTROCYTES, TO MEDIATE NEUROINFLAMMATION HAS BEEN IMPLICATED AS A SIGNIFICANT CONTRIBUTOR TO ALZHEIMER’S DISEASE PATHOGENESIS. UNFORTUNATELY, A DETAILED UNDERSTANDING OF HOW TAU AGGREGATION IS SPURRED IN THE CENTRAL NERVOUS SYSTEM (CNS) AND HOW THIS INFLUENCES NEUROIMMUNE PATHWAYS HAS REMAINED UNCLEAR. IN THE COMPLETED K99 PHASE, WE DISCOVERED A CELLULAR RECEPTOR FOR TAU UPTAKE, LRP1, AND DEVELOPED EXPERTISE IN SINGLE-CELL RNA SEQUENCING METHODS. IN THE R00 PHASE, WE WILL EXPAND ON THE KNOWLEDGE GAINED IN THE K99 MENTORED PHASE AND FOCUS THE RESEARCH ON QUESTIONS RELATED TO MICROGLIAL TAU REGULATION AND CELLULAR INFLUENCES ON TAU’S PHYSICAL STATE. IN THE FIRST HALF OF THIS PROPOSAL WE WILL EXAMINE THE MOLECULAR PATHWAYS THAT DEFINE MICROGLIAL RECOGNITION OF TAU AND DECIPHER WHICH GENES ARE MOST CRITICAL FOR THIS PROCESS. IN THE SECOND HALF WE WILL LEVERAGE OUR FUNCTIONAL GENOMICS EXPERTISE TO UNDERSTAND PATHWAYS CRITICAL FOR DE NOVO AGGREGATION OF TAU. THE NOVEL EXPERIMENTAL METHODS AND COMPREHENSIVE ANALYSES OUTLINED HEREIN WILL DEVELOP OUR UNDERSTANDING OF PATHOGENIC TAU REGULATION. FURTHER, WITH THIS MECHANISTIC INSIGHT WE WILL BE ABLE TO ENVISION NOVEL THERAPEUTIC STRATEGIES FOR DISEASES SUCH AS ALZHEIMER’S DISEASE. MANDELKOW, E. M. & MANDELKOW, E. BIOCHEMISTRY AND CELL BIOLOGY OF TAU PROTEIN IN NEUROFIBRILLARY DEGENERATION. COLD SPRING HARB PERSPECT MED 2, A006247, DOI:10.1101/CSHPERSPECT.A006247 (2012). HAROUTUNIAN, V., DAVIES, P., VIANNA, C., BUXBAUM, J. D. & PUROHIT, D. P. TAU PROTEIN ABN