Journal Article

Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation

Saroja, Sivaprakasam R., Gorbachev, Kirill, Pereira, Ana C., Goate, Alison M., Julia, TCW

2022

Overview

Tau protein aggregates are a major driver of neurodegeneration and behavioral impairments in tauopathies, including in Alzheimer’s disease (AD). Apolipoprotein E4 (APOE4), the highest genetic risk factor for late-onset AD, has been shown to exacerbate tau hyperphosphorylation in mouse models. However, the exact mechanisms through which APOE4 induces tau hyperphosphorylation remains unknown. Here, we report that the astrocyte-secreted protein glypican-4 (GPC-4), which we identify as a binding partner of APOE4, drives tau hyperphosphorylation. We discovered that first, GPC-4 preferentially interacts with APOE4 in comparison to APOE2, considered to be a protective allele to AD, and second, that postmortem APOE4-carrying AD brains highly express GPC-4 in neurotoxic astrocytes. Furthermore, the astrocyte-secreted GPC-4 induced both tau accumulation and propagation in vitro. CRISPR/dCas9-mediated activation of GPC-4 in a tauopathy mouse model robustly induced tau hyperphosphorylation. In the absence of GPC4, APOE4-induced tau hyperphosphorylation was largely diminished using in vitro tau fluorescence resonance energy transfer-biosensor cells, in human-induced pluripotent stem cell-derived astrocytes and in an in vivo mouse model. We further show that APOE4-mediated surface trafficking of APOE receptor low-density lipoprotein receptor-related protein 1 through GPC-4 can be a gateway to tau spreading. Collectively, these data support that APOE4-induced tau hyperphosphorylation is directly mediated by GPC-4.

• Publisher: National Academy of Sciences
• Subject: Alzheimer Disease - genetics / Alzheimer Disease - metabolism / Alzheimer's disease / Animal models / Animals / Apolipoprotein E / Apolipoprotein E2 - genetics / Apolipoprotein E4 / Apolipoprotein E4 - genetics / Apolipoprotein E4 - metabolism / Astrocytes / Astrocytes - metabolism / Biological Sciences / Biosensors / CRISPR / Disease Models, Animal / Energy transfer / Fluorescence resonance energy transfer / Glypicans - metabolism / Heparan sulfate proteoglycans / Human influences / Humans / Mice / Mice, Transgenic / Neurodegeneration / Neurodegenerative diseases / Neuroscience / Neurotoxicity / Phosphorylation / Pluripotency / Proteins / Receptor density / Receptors / Risk analysis / Risk factors / Stem cells / Tau protein / tau Proteins - metabolism / Tauopathies - metabolism / Tauopathies - physiopathology