The APOE4 Allele Exacerbates Pathology in a Mouse Model of Prion Disease

Abstract

AbstractBackgroundThe APOE4 allele is the strongest genetic risk factor in sporadic Alzheimer’s disease (AD). In allele‐dose dependent manner APOE4 increases AD risk, lowers age of onset, and accelerates the rate of dementia progression. Like AD, prionoses are conformational neurodegenerative disorders, which neuropathological hallmarks include accumulation of disease specific misfolded protein(s) and presence of reactive astrocytes and microglia. Accumulation of PrPSc, a toxic conformer of the cellular prion protein‐PrPC, is the initial culprit in prion pathogenesis. PrPSc buildup is associated with the presence of A1 neurotoxic astrocytes and neurodegenerative phenotype microglia (MGnD), which proinflammatory character contributes importantly to neurodegeneration in prionoses. Despite similarities between AD and prionoses, and established effects of APOE4 on misfolded protein accumulation and MGnD activation in AD, effects of the APOE genotype on prion pathology remain uninvestigated.MethodAPOE2, APOE3, and APOE4 targeted replacement mice were inoculated with 22L mouse adapted scrapie strain or normal brain homogenate (NBH) and subjected to repetitive behavioral testing. They were sacrificed at 15 or 23 weeks post inoculation (WPI), when they remained presymptomatic or showed overt neurological symptoms. Neuropathological and biochemical analyses were performed at either timepoint, while NanoStringTM analysis of microglia and astrocyte transcriptomic markers was done at 23WPI.ResultAPOE4 mice feature significantly shorter incubation period and more severe burden of neurological symptoms following prion inoculation than APOE2 and APOE3 mice. Neuropathological analysis reveals significantly higher burden of spongiforms changes in the brain cortex and greater load of reactive astrocytes and microglia in APOE4 mice compared to other APOE genotypes. APOE4 mice also show the highest level of total PrP and PrPSc and insoluble/soluble PrP index. Transcriptomic analysis reveals prion inoculation effects marked elevation of PAN and A1 reactive astrocyte markers, MGnD markers, and in pro‐inflammatory chemokines and cytokine receptors transcripts across all APOE genotypes but the NBH‐relative increase is the highest in APOE4 mice.ConclusionThe APOE4 allele promotes prion neurodegeneration through two separate mechanisms. It is associated with greater PrPSc accumulation and toxicity suggesting its role in the PrPSc metabolism and clearance. It also promotes acquisition of A1 and MGnD neurotoxic phenotypes by astrocytes and microglia, respectively.