TRANSCRIPTIONAL ANALYSIS AND FUNCTIONAL MODULATION OF MEMORY NEURAL CIRCUITS IN ALZHEIMER’S DISEASE

ALZHEIMER’S DISEASE (AD) IS CHARACTERIZED BY PROGRESSIVE MEMORY LOSS AND NEUROSYCHIATRIC SYMPTOMS ASSOCIATED WITH CELL-SPECIFIC PATHOLOGICAL FEATURES IN VULNERABLE NEURAL CIRCUITS. DISRUPTION OF EXCITATORY GLUTAMATERGIC AND INHIBITORY SYNAPTIC TRANSMISSION WAS RECENTLY POSTULATED TO CONTRIBUTE TO EXCITATORY/INHIBITORY IMBALANCE IN MEMORY NEURAL CIRCUITS IN AD AND DEMENTIA, BUT THE NEURONAL MECHANISMS THAT LINK AD NEUROPATHOLOGICAL FEATURES WITH FUNCTIONAL CHANGES OF EXCITATORY GLUTAMATERGIC AND INHIBITORY PARVALBUMIN NEURONS AND MEMORY LOSS REMAIN LARGELY UNKNOWN. OUR RECENT STUDIES DEMONSTRATE A COOPERATIVE NEGATIVE EFFECT BETWEEN TAU AND AB ON SYNAPTIC PLASTICITY, NEURONAL ACTIVATION, AND MEMORY IN NOVEL DOUBLE APP/TAU TRANSGENIC MICE THAT DEVELOP B-AMYLOID, TAU AND SYNAPSE PATHOLOGIES. IMPORTANTLY, DEREGULATION OF TRANSCRIPTIONAL NETWORKS IN DISTINCT CELL TYPES ARE ASSOCIATED WITH SYNAPSE PATHOLOGY AND MEMORY DEFICITS AT EARLY AD PATHOLOGICAL STAGES, BUT THE EXCITATORY AND INHIBITORY TRANSCRIPTIONAL PROGRAMS THAT CONTRIBUTE TO ALTERATION OF MEMORY NEURAL CIRCUITS IN AD ARE UNKNOWN. HERE, WE HYPOTHESIZE THAT DEREGULATION OF KEY TRANSCRIPTIONAL PROGRAMS IN EXCITATORY AND INHIBITORY NEURONS UNDERLIE SELECTIVE NEURONAL VULNERABILITY IN MEMORY NEURAL CIRCUITS IN AD. IN THIS PROJECT, WE AIM TO INVESTIGATE THE TRANSCRIPTIONAL PROGRAMS OF EXCITATORY (GLUTAMATERGIC) AND INHIBITORY (PARVALBUMIN) NEURONS LINKED WITH MEMORY LOSS IN AD. WE WILL EMPLOY CUTTING-EDGE UNBIASED CELL-SPECIFIC AND SPATIAL TRANSCRIPTOMICS, BIOINFORMATIC GENE INTEGRATIVE ANALYSES AND IN VIVO NEURONAL ACTIVITY AND CHEMOGENETIC/GENE THERAPY APPROACHES IN NOVEL APP/TAU RIBO_TAG (ATARI) TRANSGENIC MICE. THE OBJECTIVES OF THIS PROJECT ARE: 1) TO IDENTIFY HIPPOCAMPAL EXCITATORY AND INHIBITORY TRANSCRIPTIONAL PROGRAMS THAT CONTRIBUTE TO EARLY MEMORY LOSS IN APP/TAU TRANSGENIC MICE; 2) TO MODULATE THE ACTIVITY OF HIPPOCAMPAL EXCITATORY NEURAL CIRCUITS TO AMELIORATE AND/OR REVERSE AD-RELATED PATHOLOGICAL, TRANSCRIPTIONAL AND MEMORY CHANGES. THE RESULTS OF THIS PROJECT ARE CRITICAL TO BETTER UNDERSTAND HOW THE NEUROPATHOLOGICAL FEATURES TAU AND B-AMYLOID ARE INVOLVED IN THE SPECIFIC NEURONAL VULNERABILITY UNDERLYING DYSFUNCTION OF NEURAL MEMORY CIRCUITS IN AD, A KEY STEP TO DEVELOP NOVEL PERSONALIZED DIAGNOSTIC AND THERAPEUTIC STRATEGIES FOR DEMENTIA.