TY - JOUR
T1 - Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease
AU - McAlpine, Cameron S.
AU - Park, Joseph
AU - Griciuc, Ana
AU - Kim, Eunhee
AU - Choi, Se Hoon
AU - Iwamoto, Yoshiko
AU - Kiss, Máté G.
AU - Christie, Kathleen A.
AU - Vinegoni, Claudio
AU - Poller, Wolfram C.
AU - Mindur, John E.
AU - Chan, Christopher T.
AU - He, Shun
AU - Janssen, Henrike
AU - Wong, Lai Ping
AU - Downey, Jeffrey
AU - Singh, Sumnima
AU - Anzai, Atsushi
AU - Kahles, Florian
AU - Jorfi, Mehdi
AU - Feruglio, Paolo Fumene
AU - Sadreyev, Ruslan I.
AU - Weissleder, Ralph
AU - Kleinstiver, Benjamin P.
AU - Nahrendorf, Matthias
AU - Tanzi, Rudolph E.
AU - Swirski, Filip K.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/7/29
Y1 - 2021/7/29
N2 - Communication within the glial cell ecosystem is essential for neuronal and brain health1–3. 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 interactions4,5. 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.
AB - Communication within the glial cell ecosystem is essential for neuronal and brain health1–3. 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 interactions4,5. 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.
UR - http://www.scopus.com/inward/record.url?scp=85111653296&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-03734-6
DO - 10.1038/s41586-021-03734-6
M3 - Article
C2 - 34262178
AN - SCOPUS:85111653296
SN - 0028-0836
VL - 595
SP - 701
EP - 706
JO - Nature
JF - Nature
IS - 7869
ER -