How missing APOE4 protects

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Science  23 Apr 2021:
Vol. 372, Issue 6540, pp. 357-358
DOI: 10.1126/science.372.6540.357-g

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer's disease. Alzheimer's pathology involves both β-amyloid aggregation and phosphorylated tau–dependent neurodegeneration. The APOE4 variant is associated with worse tauopathy and neurodegeneration. In the brain, apoE is produced and secreted primarily by astrocytes and activated microglia. Wang et al. produced a transgenic tauopathy mouse model in which APOE4 (or APOE3 as a control) could be specifically down-regulated in astrocytes after disease onset. Removing astrocytic apoE4 reduced tau-mediated neurodegeneration and suppressed disease-associated gene expression in neurons, oligodendrocytes, astrocytes, and microglia. Furthermore, removal of astrocytic apoE4 decreased tau-induced synaptic loss and phagocytosis of synaptic elements by microglia. These findings shed light on the potential mechanisms underlying how and why APOE4 exacerbates Alzheimer's disease.

Neuron 10.1016/j.neuron.2021.03.024 (2021).

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