Project Summary Alzheimer’s disease (AD) is the most common cause of progressive dementia in older adults, but there is no cure for this debilitating condition. We hypothesize that aging and AD-related pathologies cause maladaptive changes within hippocampal formation circuits that serve as connectome hubs for large numbers of critical brain regions, ultimately leading to age- and AD-related cognitive deficits. In response to RFA-AG-22-008, we have assembled a strong multi-investigator team across multiple institutions with complementary expertise in neural circuit mapping, next-generation AD mouse model development, single-cell transcriptomics and epigenomics analysis, and mouse brain common coordinate framework / atlas development. We will leverage the exceptional resources offered by the UCI Center for Neural Circuit Mapping, the MODEL-AD Consortium and the Allen Institute for Brain Science. We propose to perform large-scale, cell-type-specific mapping of hippocampal formation circuits to generate cellular resolution connectome data that combines molecular and anatomical annotations. To capture a more accurate composite of human AD features, we will use three complementary AD mouse models including two next-generation AD mouse models. These include 1) the 5xFAD mouse model with familial mutations, 2) the hAß-KI mouse that expresses human wild-type Aβ sequence from the endogenous mouse App locus to model late-onset AD features, and 3) Trem2 R47H knock-in mice that model the increased risk of the R47H coding variant for late onset AD. We will comprehensively map and characterize hippocampal formation brain circuits, including CA1, the subiculum (SUB) and the entorhinal cortex (EC) that show earliest neurodegeneration across AD mouse models and in human patients. These sub-circuits serve as hubs for neural processing from many other cortical and sub-cortical brain regions. We will use genetically modified transsynaptic neurotropic viruses developed by our team to map brain-wide anterograde and retrograde neural networks. The brain connectomes generated from viral tracing experiments will be enhanced with spatially resolved, single-cell transcriptomics-based molecular annotation using MERFISH (multiplexed error-robust fluorescence in situ hybridization). We will identify molecular candidates that confer vulnerability versus disease resistance as we superimpose spatial transcriptomic data on AD-modulated circuit connectomes. The entire data set will be annotated using the Allen Mouse Brain Common Coordinate Framework to facilitate resource and data sharing. Our work will improve our understanding of brain circuits susceptible to aging and AD towards developing better early diagnostic tools and new treatment strategies for AD.

Project Narrative Alzheimer's disease (AD) is an escalating major health concern in the United States. The proposed research will use cutting-edge neuroscience techniques to map vulnerable cell types and neural connectivity changes using mouse models of aging and AD. Our research meets multiple major goals of RFA-AG-22-008 and is expected to have high impact by providing critical reference information for molecular and neural circuit studies of multiple established and new AD models for the large AD research community.