Multiscale Modeling of Hippocampus Vulnerability to Alzheimer's Disease Neurodegeneration.

/Abstract Neurodegeneration of the hippocampus is believed to be associated with cognitive decline in patients with Alzheimer’s disease (AD). Cognition is considered to be an emergent brain function resulting from neural network level computation rather than individual cellular processing, but exactly how AD cognitive impairment results from progressive disconnection of hippocampal networks due to cellular level neurodegeneration is unclear. Which neurons and how many neurons must be lost before cognitive symptoms become apparent? Multiscale computational models that can incorporate these brain features are critical but require spatially precise cell type-specific datasets across multiple progressive disease timepoints. Our previous work creating the Hippocampus Gene Expression Atlas (HGEA) integrated gene expression and connectivity data to define neuronal cell types in 20 spatio-molecular domains across the entire mouse hippocampus, delineated the hippocampal connectome wiring diagram, and revealed the hippocampus as a multiscale hierarchical network that contributes to brain-wide networks regulating cognition, social behaviors, and neuroendocrine function. Building on the HGEA dataset and our team’s unique expertise in the hippocampus and multiscale computational modeling, we propose to develop HGEA-NET, a new multiscale computational model of the hippocampus containing the HGEA-defined neuronal cell types and their cell type specific gene expression and connectivity. We hypothesize that the progressive degeneration of specific AD susceptible neuronal cell types leads to hippocampal network dysfunction associated with cognitive decline across longer disease timepoints. In this project, we will use Multiplexed Error Robust Fluorescent In Situ Hybridization (MERFISH) spatial transcriptomics and viral connectomics approaches to investigate neurodegenerative changes to hippocampal cell type gene expression and circuit connectivity in 5xFAD mice AD models and human AD post-mortem tissue samples with varying degrees of cognitive impairment. By incorporating these data into the HGEA-NET, we will determine which hippocampal neurons and their connections appear susceptible and simulate how the disconnection of these cell types in the multiscale model leads to network dysfunction related to cognitive impairment. Overall, the successful development of HGEA-NET will provide major impact as a new translational drug development virtual testbed for the treatment of cognitive dementia in AD. Project Number: 1R01AG092662-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Michael Bienkowski | Institution: UNIVERSITY OF SOUTHERN CALIFORNIA, Los Angeles, CA | Award Amount: $695,789 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZAG1 ZIJ-P (J1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11116518