Effect of APOE on CNS Neurons: Role of LRP
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PROJECT SUMMARY/ABSTRACT APOE genotype is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). The ε4 allele of APOE increases risk for AD by ~3.7 fold for one allele and by ~12-15 fold for 2 alleles relative to ε3 homozygotes, while one copy of the ε2 allele decreases the risk for AD by ~50%. In addition, recent data have shown that rare APOE variants protect against either late-onset AD (V236E and R251G) or against autosomal dominant AD (APOE3 Christchurch (Ch) R136S). A complete understanding of apoE’s role in AD pathogenesis remains unclear. In addition to effects of apoE on Aβ aggregation and clearance, apoE is also highly likely to influence risk for or progression of AD via additional mechanisms. The main recent work on this grant has been to determine whether and how apoE influences amyloid-induced tau seeding/spreading, tau pathology, neurodegeneration, and the brain’s innate/adaptive immune response. There is robust evidence that Aβ accumulation drives the “spreading” of tau pathology but how this happens is not well understood. In addition, the neuronal and synaptic loss that occurs in AD correlates well with the location and accumulation of tau pathology. We have shown that apoE produced by astrocytes plays a key role in Aβ deposition and that apoE4 strongly contributes to tau-mediated neurodegeneration. We have also found that microglia suppress Aβ- mediated tau seeding and spreading and that apoE isoforms can strongly regulate this effect. Interestingly, the apoE3Ch variant strongly suppresses Aβ-induced tau seeding and spreading with the effects appearing to potentially occur via microglial apoE receptors. We also found that once tau-mediated neurodegeneration begins, microglia can exacerbate neurodegeneration which is strongly influenced by apoE with apoE4 worsening this and lower levels of apoE leading to less injury. Tau-mediated neurodegeneration is associated with large increases in microglial cholesterol esters and other lipids that is associated with endosomal/ lysosomal defects. Our data suggests that apoE is at the nexus of how Aβ induces tauopathy and how tauopathy leads to neurodegeneration. This and other data lead us to hypothesize that apoE variants affect 1) uptake and degradation of aggregated tau via competitive interactions with HSPG-LRP1 and 2) microglial lysosomal function. These effects of apoE variants and the HSPG-LRP1 pathway then impact Aβ-induced tau seeding and spreading as well as tau-mediated neurodegeneration and lysosomal lipid accumulation. This hypothesis will be evaluated in the following aims: Aim 1: To determine if LRP1 in microglia or neurons mediates the effect of apoE isoforms on Aβ-induced tau seeding and spreading Aim 2: To determine if LRP1 in microglia or neurons mediates the effect of apoE on tau-mediated neurodegeneration. Aim 3: To determine whether and how apoE variants influence microglial lysosomal function, lipid accumulation and activation state as well as LRP1-dependent tau uptake and clearance.
