Role of APOE in endosomal processing of alpha-synuclein

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Role of APOE in endosomal processing of alpha-synuclein Dementia is among the most harmful and costly aspects of Lewy body disease (LBD) which is comprised of Parkinson disease (PD) and dementia with Lewy bodies (DLB) and shares some clinical features with Alzheimer’s disease. In particular, dementia and psychosis are often early and aggressive symptoms in patients with DLB. Pathologically, these illnesses share the feature of aggregation of misfolded forms of the protein alpha-synuclein (aSyn), termed Lewy bodies, which spread throughout multiple brain regions during the disease and are toxic to cells. In addition to Lewy bodies, patients with LBD often have amyloid plaques and neurofibrillary tangles which are hallmarks of Alzheimer’s disease, and patients with Alzheimer’s disease often have Lewy bodies in addition to plaques and tangles. The exact mechanism of how aSyn becomes misfolded and why cognitive decline is accelerated in DLB is unclear. Genetic studies point to a strong link between increased DLB risk and the APOE4 variant of the gene that encodes apolipoprotein E, another protein that is also central to Alzheimer’s disease risk. We reported that mice expressing the APOE4 version of the human APOE gene had accelerated aSyn aggregation and early death compared to other APOE genotypes. This finding is similar to the effects observed when human APOE genotypes are expressed in mouse models of Alzheimer’s disease. Our preliminary data indicate that astrocytes and microglia take up aSyn aggregates and process them through the endolysosomal pathway, which may serve as a compensatory mechanism to degrade harmful aSyn aggregates. We propose to examine the cell biological transit of aSyn aggregates through the endolysosomal pathway in astrocytes and microglia and determine if there are differences in this trafficking related to APOE genotype. We hypothesize that the APOE4 genotype impairs endolysosomal degradation of aSyn aggregates in both astrocytes and microglia, and that astrocyte expression of APOE4 in particular drives accelerated aSyn pathology leading to brain dysfunction and neurodegeneration. We will test whether this effect occurs mainly due to cell-autonomous changes within astrocytes or microglia themselves, including related to changes in gene expression in those cells, or whether it is mediated through secreted apolipoprotein E protein particles that are known to have effects by binding to receptors on both neurons and glia. The main goal of these experiments is to clarify how APOE genotype regulates endolysosomal processing of aSyn in astrocytes and microglia and how this knowledge can be leveraged to develop novel treatments for DLB, Alzheimer’s disease, and other related dementias.