Astrocytic Interleukin-3 Programs Microglia and Limits Alzheimer's Disease

Overview

Journal Nature

Specialty Science

Date 2021 Jul 15

PMID 34262178

Citations 136

Authors

Cameron S McAlpine

Joseph Park

Ana Griciuc

Eunhee Kim

Se Hoon Choi

Yoshiko Iwamoto

Mate G Kiss

Kathleen A Christie

Claudio Vinegoni

Wolfram C Poller

John E Mindur

Christopher T Chan

Shun He

Henrike Janssen

Lai Ping Wong

Jeffrey Downey

Sumnima Singh

Atsushi Anzai

Florian Kahles

Mehdi Jorfi

Paolo Fumene Feruglio

Ruslan I Sadreyev

Ralph Weissleder

Benjamin P Kleinstiver

Matthias Nahrendorf

Rudolph E Tanzi

Filip K Swirski

Affiliations

Soon will be listed here.

Abstract

Communication within the glial cell ecosystem is essential for neuronal and brain health. The influence of glial cells on the accumulation and clearance of β-amyloid (Aβ) and neurofibrillary tau in the brains of individuals with Alzheimer's disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Upon recognition of Aβ deposits, microglia increase their expression of IL-3Rα-the specific receptor for IL-3 (also known as CD123)-making them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional programming of microglia to endow them with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of Aβ and tau. These changes restrict AD pathology and cognitive decline. Our findings identify IL-3 as a key mediator of astrocyte-microglia cross-talk and a node for therapeutic intervention in AD.

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