This is a summary of Kaji, S., Berghoff, S., Spieth, L., et al (2024). Apoliprotein E aggregation in microglia initiates Alzheimer’s disease pathology by seeding β-amyloidosis. Published in Immunity https://doi.org/10.1016/j.immuni.2024.09.014
The challenge
Alzheimer’s disease (AD) begins with a preclinical phase characterized by the accumulation of insoluble amyloid-β (Aβ), which forms extracellular plaques. This gradual build-up of amyloid plaques is believed to initiate a series of pathological events involving various cell types. These events ultimately lead to neurodegeneration, resulting in a progressive decline in memory and cognitive function. However, how this pathological cascade is initiated is not fully understood. What is known is that the major genetic risk factor for sporadic AD is the APOE4 allele of the Apolipoprotein E (APOE), which was, therefore, the focus of our research.
Our approach
Highly sensitive detection and biochemical purification of APOE allowed us to analyze its structure, localization, and function in the initiation and seeding of amyloid aggregates. Specifically, we utilized a new APOE-Halo 5xFAD mouse model that facilitates the visualization and isolation of APOE.
Our findings
We isolated APOE aggregates from mouse models of amyloidosis and AD patients. Our study indicates that these fibrillary aggregates of APOE may act as seeds for Aβ plaque formation. This aggregation appears to occur within the lysosomal system of microglia and is linked to cholesterol metabolism. Additionally, lysosomal dysfunction and pro-inflammatory activation contribute to aggregate formation in microglia.
The implications
Our results suggest that endocytic uptake and lysosomal aggregation of APOE by microglia can initiate Aβ plaque formation and is modulated by immune and lipid metabolism. Thus, blocking APOE aggregation or its targeting to microglia may represent a therapeutic strategy to prevent or delay the formation of amyloid plaques. Additionally, our study underscores the importance of innate immune mechanisms in the initiation of AD, and provides opportunities for future translational studies in humans.
Creating SyNergies
Apart from the lead of this study, Mikael Simons, the Synergy members Sarah Jäkel, Christian Haass, Wolfgang Wurst, and Martina Schifferer were involved in this study and provided resources and technologies.