IDENTIFICATION OF ALZHEIMER'S-SPECIFIC TAU ALTERATIONS

ALZHEIMER'S DISEASE (AD) IS A DEVASTATING ILLNESS CURRENTLY AFFECTING OVER 2.5 MILLION PEOPLE IN THE UNITED STATES, WITHFINANCIAL COSTS FOR DIAGNOSIS AND LONG-TERM CARE EXCEEDING $50 BILLION ANNUALLY. THE ETIOLOGY OF AD IS UNKNOWN, BUT ITS TWO BIOCHEMICAL HALLMARKS ARE THE PRESENCE OF EXTRACELLULAR PLAQUE AND INTRACELLULAR NEUROFIBRILLARY TANGLES (NFT) IN THE BRAINS OF AFFECTED INDIVIDUALS. THE GROSS CELLULAR DISTORTIONS ACCOMPANYING THE ACCUMULATIONOF INTRANEURONAL NFT UNDOUBTEDLY DISRUPT CYTOSKELETAL ARCHITECTURE AND CELLULAR TRANSPORT AND CONTRIBUTE TO NEURONAL DEATH. THE MICROTUBULE-ASSOCIATED PHOSPHOPROTEIN TAU PROMOTES THE ASSEMBLY OF TUBULIN INTO MICROTUBULES, AND TAU HAS BEEN SHOWN TO BE THE MAJOR ANTIGENIC COMPONENT OF NFT; HOWEVER, THE STRUCTURAL ALTERATIONS IN TAU RESPONSIBLE FOR ITS INCORPORATION INTO NFT ARE UNKNOWN. IN PHASE I, IT IS PLANNED TO ISOLATE TAU FROM AD AUTOPSIED BRAINS AND CHARACTERIZE THESE DISEASE-SPECIFIC MODIFICATIONS. THE ELUCIDATION OF THESE ALTERATIONS WILL SHED GREATER LIGHT ON THE ABERRANT BIOCHEMICAL EVENTS LEADING TO NEURONAL DESTRUCTION IN AD AND MAY HAVE IMPORTANT IMPLICATIONS IN OTHER AGE-RELATED NEURODEGENERATIVE DISEASES WHERE NFT FORMATION IS SYMPTOMATIC. THE ULTIMATE GOAL IS TO DEFINE THE BIOCHEMICAL PATHWAY LEADING TO NFT FORMATION TO PERMIT THE DESIGN OF A THERAPEUTIC DRUG THAT WILL INHIBIT THE ABERRANT BIOCHEMICAL EVENT(S) LEADING TO NEURONAL DESTRUCTION.