Apolipoprotein E4 drives tau propagation through astrocyte‐secreted glypican‐4. (December 2021)

• Record Type: Journal Article
• Authors: Pereira, Ana C.; Saroja, Sivaprakasam
• Is Part Of: Alzheimer's & dementia. Volume 17(2021)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.054243
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Apolipoprotein E4 (APOE4) is the most crucial genetic risk factor of late‐onset Alzheimer's disease (AD). However, the mechanism through which APOE4 induces AD risk remains unknown. Methods: We have utilized post‐mortem AD brain tissues of APOE variants, biochemical assays and a series of in vitro and in vivo experiments with transgenic mouse models to study the role of GPC‐4 in APOE4 induced tau pathology. Results: Here, we report the astrocyte‐secreted protein glypican‐4 (GPC‐4), as a novel binding partner of APOE4, drives tau pathology. APOE4‐carrying post‐mortem AD brain tissue display more tau accumulation compared to APOE4‐noncarring AD patients. GPC‐4 is highly expressed in APOE4 post‐mortem AD brains and regulated by microglial factors via NF‐κB signaling pathway. The astrocyte‐secreted GPC‐4 induced both tau accumulation and spreading in vitro and in vivo animal models . Further, GPC‐4 is required for APOE4‐mediated surface trafficking of low‐density lipoprotein receptor‐related protein 1 (LRP1) and tau propagation. GPC‐4 activates unfolded protein response (UPR) pathway IRE1α, and pharmacological inhibition of IRE1α with KIRA6 blocks GPC‐4 induced tau propagation in in vivo animal models. Conclusions: Together, our data demonstrate that one of the APOE4‐induced AD risk is directly mediated by GPC‐4, and that perturbing GPC‐4 induced IRE1α pathway has therapeutic opportunities.