Featured Faculty Papers

 

Fall 2021 ARTICLE - Dr. Nicholas Fitz

Phospholipids of APOE lipoproteins activatemicroglia in an isoform-specific manner inpreclinical models of Alzheimer’s disease

 

Nicholas F. Fitz, Kyong Nyon Nam, Cody M. Wolfe, Florent Letronne, Brittany E. Playso, Bistra E. Iordanova, Takashi D. Y. Kozai, Richard J. Biedrzycki, Valerian E. Kagan, Yulia Y. Tyurina, Xianlin Han, Iliya Lefterov & Radosveta Koldamova

APOE and Trem2 are major genetic risk factors for Alzheimer’s disease (AD), but how theyaffect microglia response to Aβremains unclear. Here we report an APOE isoform-specificphospholipid signature with correlation between human APOEε3/3 and APOEε4/4 AD brainand lipoproteins from astrocyte conditioned media of APOE3 and APOE4 mice. Using pre-clinical AD mouse models, we show that APOE3 lipoproteins, unlike APOE4, induce fastermicroglial migration towards injected Aβ, facilitate Aβuptake, and ameliorate Aβeffects oncognition. Bulk and single-cell RNA-seq demonstrate that, compared to APOE4, corticalinfusion of APOE3 lipoproteins upregulates a higher proportion of genes linked to an acti-vated microglia response, and this trend is augmented by TREM2 deficiency. In vitro, lack ofTREM2 decreases Aβuptake by APOE4-treated microglia only, suggesting TREM2-APOEinteraction. Our study elucidates phenotypic and transcriptional differences in microglialresponse to Aβmediated by APOE3 or APOE4 lipoproteins in preclinical models of AD

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