Project Grant R36AG087310

CA1 CELL-TYPE SUSCEPTIBILITY IN ALZHEIMER'S - ABSTRACT ADVANCED NEUROIMAGING TECHNIQUES HAVE SHOWN THE IMPACTS OF ALZHEIMER'S DISEASE (AD) PATHOLOGY PROPAGATION AND THEIR STRUCTURAL REPERCUSSIONS IN THE BRAIN. RECENT STUDIES SHOW THAT UNIMPAIRED INDIVIDUALS WHO HAVE ADVANCED AMYLOID AND TAU PATHOLOGY IN THE MEDIAL TEMPORAL LOBE (MTL) ARE MORE AT RISK FOR DEVELOPING MILD COGNITIVE IMPAIRMENT (MCI). THESE DISCOVERIES SUGGEST THE PRESENCE OF VULNERABLE BRAIN REGIONS THAT SERVE AS AN INITIAL FOCAL POINT FOR THE SPREAD OF AD PATHOLOGY. RECENT DEVELOPMENTS IN CONNECTOMICS AND SPATIAL TRANSCRIPTOMICS NOW ALLOW US TO IDENTIFY INDIVIDUAL CELL TYPES WITHIN THE MTL AND INVESTIGATE THE SUBCELLULAR MOLECULAR CHANGES THAT OCCUR THROUGHOUT AD PROGRESSION. IDENTIFYING SUSCEPTIBLE CELL TYPES WITHIN MTL WILL REVEAL POTENTIAL TARGETS FOR EARLY TREATMENT INTERVENTION. WITHIN THE MTL, ENTORHINAL CORTEX (ENT) CONNECTIONS WITH CA1 IN THE HIPPOCAMPUS ARE PARTICULARLY AFFECTED BY AD AND RELATED TO COGNITIVE IMPAIRMENT. FROM CA1, IT IS BELIEVED THAT AMYLOID AND TAU PROPAGATE THROUGH NEURAL CIRCUITS TO OTHER BRAIN STRUCTURES, LEADING TO A NEURODEGENERATIVE CASCADE AS IT EXTENDS TO ADDITIONAL BRAIN REGIONS. ESTABLISHING AND CHARACTERIZING DISTINCT NEURONAL CHANGES IN CA1 PROJECTION NEURON CELL TYPES, IN THE PRESENCE OF AMYLOID, CAN REVEAL NOVEL TARGETS WITH THE AIM OF MITIGATING OR EVEN HALTING THE PROGRESSION OF AD AT ITS EARLIEST STAGES. WE HYPOTHESIZE THAT A NEURAL CIRCUIT FROM ENTORHINAL CA1 NEURONS THAT PROJECT TO OTHER MEMORY-RELATED BRAIN STRUCTURES ARE SPECIFICALLY SUSCEPTIBILITY POINTS TO AD. TO UNVEIL VULNERABLE CA1 NEURONS AND UNDERSTAND ALTERATIONS IN THEIR MORPHOLOGICAL CHARACTERISTICS, WE WILL USED ADVANCED VIRAL TRACING METHODS AND CUTTING-EDGE MICROSCOPY IMAGING TO IDENTIFY AND RECONSTRUCT 3D ENTCA1 CELL-TYPE SPECIFIC CIRCUITS TO ANALYZE DISTINCT PATHWAY CHANGES IN AD MOUSE MODELS. AFTER IDENTIFYING SUSCEPTIBLE CELL TYPES, WE WILL USE MERFISH SPATIAL TRANSCRIPTOMICS TO INVESTIGATE THE MOLECULAR CHANGES TO AD-RELEVANT GENES WITHIN CA1 NEURONS. OVERALL, THIS STUDY WILL ESTABLISH CELL TYPE SPECIFIC NEURAL CIRCUITS THAT ARE SUSCEPTIBLE TO AD PATHOLOGY AND REVEAL THE SUBCELLULAR RESPONSE OF THESE CELL TYPES THROUGHOUT THE PROGRESSION OF DISEASE.