Abstract
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. Here, we report the astrocyte-secreted protein glypican-4 (GPC-4), as a novel binding partner of APOE4, drives tau pathology. APOE4-carrying AD patients display more tau accumulation compared to APOE4-noncarring AD patients. GPC-4 is highly expressed in APOE4 AD patients, and is 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. 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. Together, our data comprehensively demonstrate that the APOE4-induced AD risk is directly mediated by GPC-4, and that perturbing GPC-4 induced IRE1α pathway has therapeutic opportunities.
Highlights
Apolipoprotein (APOE) plays a major role in the circulation of high-density and very-low-density lipoproteins and mediates the transport of fats between the cells 1
Human Apolipoprotein E4 (APOE4)/4 Alzheimer’s patients display more tau accumulation The abnormal posttranslational modification of tau protein is associated with formation of neurofibrillary tangles and prion-like propagation of tau proteins [24,25]. Both Alzheimer’s disease (AD) mouse models and human AD PET images suggest the abnormal tau as a major driver of cerebral atrophy, and APOE4 carrying AD patients display a severe atrophy compared to APOE4 noncarriers [19,22]
Glypican-4 drives APOE4-mediated tau propagation Given that both APOE4 and GPC-4 enhanced tau pathology, we examined whether the differential efficacy of APOE2 and APOE4 is dependent on the GPC-4 interaction
Summary
Apolipoprotein (APOE) plays a major role in the circulation of high-density and very-low-density lipoproteins and mediates the transport of fats between the cells 1. APOE is secreted by glial cells, primary astrocytes 2. Cholesterol released by astrocytes in the form of APOEcontaining high-density lipoprotein-like particles are vital for neuronal survival 3. Human APOE is expressed in three genetic variants; APOE2, APOE3, and APOE4. These variants differ in terms of position of two amino acid residues; APOE3 has a cysteine at position 112 and arginine at position 158, APOE2 has a cysteine at both positions, and APOE4 has an arginine at both position 4. Among the three APOE isoforms, APOE4 is the most crucial genetic risk factor for late-onset Alzheimer’s disease (AD). APOE2 carriers have a lower likelihood of developing AD; APOE2 protects against AD 5–10
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