Neuronal ApoE Drives Selective Neurodegeneration in Alzheimer's Disease

PROJECT SUMMARY Selective neurodegeneration is a critical causal factor in Alzheimer’s disease (AD); however, the mechanisms that lead some neurons to perish while others remain resilient are unknown. There is regional susceptibility to AD-related neurodegeneration in the hippocampus and entorhinal cortex. Even within vulnerable neuronal populations, however, some cells are lost early while others prove more resilient. With recent technical improvements in single-cell analysis, we are able for the first time to examine the variability that drives regional and cellular differences in susceptibility to neurodegeneration. The major genetic risk factor for Alzheimer’s disease is apolipoprotein E4 (apoE4), which increases disease risk and decreases age of onset in carriers. Within the central nervous system, apoE is produced primarily in astrocytes but also in neurons following stress, injury, and aging. Neuronal apoE4 expression diminishes synaptic plasticity, impairs synaptogenesis, and decreases synaptic density both in vitro and in vivo. This proposal is based on intriguing preliminary studies. (1) Single-nucleus RNA-sequencing data from our lab have revealed a link between neuronal apoE and neuronal expression of the major histocompatibility complex class I (MHC-I). Like apoE, MHC-I is expressed in neurons following stress, injury, and aging. Neuronal MHC-I is localized to post-synaptic densities, where they limit long-term potentiation, enhance long term depression, and mediate synaptic pruning during development and, potentially, in neurodegenerative diseases. Our discovery of neuronal apoE upregulation of MHC-I provides insight into the mechanism by which both proteins potentially work in concert to contribute to synapse loss and eventually to selective neurodegeneration. (2) In AD patients, neuronal apoE expression correlates with neuronal MHC-I expression, which in turn predicts severity of Tau pathologies. (3) In AD model mice or cultured primary neurons, neuron-specific apoE4 knock-out decreases neuronal MHC-I expression and rescues neuronal and synaptic loss, establishing a causal relationship between neuronal apoE, upregulation of MHC-I, and selective neurodegeneration in AD. To capitalize on these novel findings and recent technical improvements in single-cell analyses, this proposal aims to determine the apoE-expression-high and MHC-I-expression-high neuron populations and explore their relationships with selective neurodegeneration across AD-susceptible and AD-resistant brain regions of apoE- KI mice with different apoE genotypes at different ages (Aim 1). We will also determine how apoE is regulating neuronal expression of MHC-I and how this expression leads to Alzheimer’s disease-related pathologies (Aim 2). Finally, we propose to determine the extent to which this apoE and MHC-I-mediated neuronal loss is caused by signaling to microglia (Aim 3), which has been heavily implicated in Alzheimer’s disease pathogenesis. The outcome of the proposed studies should shed light on the mechanisms underlying regional, cell-type-specific, and within-cell-type selective vulnerability to Alzheimer’s disease.