Intrinsic antiviral immunity drives neurodegeneration in Alzheimer disease
Stefano Pluchino, Cory Willis
Stefano Pluchino, Cory Willis
Published March 9, 2020
Citation Information: J Clin Invest. 2020;130(4):1622-1624. https://doi.org/10.1172/JCI135906.
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Commentary

Intrinsic antiviral immunity drives neurodegeneration in Alzheimer disease

Abstract

β-Amyloid aggregates found in brain plaques are viewed as triggers of cytotoxicity and neuroinflammation in Alzheimer disease (AD). However, the main β-amyloid (Aβ) species and what imbues the aggregates with such toxic potential are still not yet understood. In this issue of the JCI, Roy et al. show that Aβ complexed with nucleic acids triggers an antiviral type I interferon response in neuroglia, resulting in complement-mediated synapse elimination in AD models. These findings identify a putative endogenous immune signaling axis that drives neurodegeneration in AD and has strong implications for the development of precise therapeutic strategies.

Authors

Stefano Pluchino, Cory Willis

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Figure 1

Model of type I IFN–mediated neuroinflammation and synapse loss in AD.

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Model of type I IFN–mediated neuroinflammation and synapse loss in AD. N...
NA+ amyloid induces a type I ISG signature leading to increased IFN-β secretion, predominantly in microglia. Type I IFNs act via IFN-α/β receptors (IFNARs) to induce type I IFNs and AD-related proinflammatory factors, such as C3 in astrocytes. Other microglia gene markers are also upregulated. Autocrine and paracrine signaling perpetuates cell activation and drives synapse loss and neurodegeneration.