Neuronal ApoE Upregulates MHC-I Expression to Drive Selective Neurodegeneration in Alzheimer’s Disease

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. We sought potential drivers of this selective vulnerability­ using single-nucleus RNA sequencing and discovered that apoE expression level is a substantial driver of neuronal variability. Strikingly, neuronal expression of apoE—which has a robust genetic linkage to AD—correlated strongly, on a cell-by-cell basis, with immune response pathways in neurons in the brains of wildtype mice, human apoE knock-in mice, and humans with or without AD. Elimination or over-expression of neuronal apoE revealed a causal relationship between apoE expression, neuronal MHC-I expression, Tau pathology, and neurodegeneration. Functional reduction of MHC-I ameliorated Tau pathology in apoE4-expressing primary neurons and in mouse hippocampi expressing pathological Tau. These findings suggest a mechanism linking neuronal apoE expression to MHC-I expression and, subsequently, to Tau pathology and selective neurodegeneration. Single-nucleus RNA sequencing of hippocampus from human APOE3 targeted replacement mice at 5, 10, 15, and 20 months, human APOE4 targeted replacement mice at 5, 10, 15, and 20 months, and neuron-specific APOE-KO (Syn-cre x floxed APOE) mice at 10 and 15 months.