DOI: 10.1002/alz.076510 ISSN: 1552-5260

APOE4 impairs microglia‐astrocyte response in Alzheimer’s disease by inducing TGFβ‐mediated checkpoints

Oleg Butovsky, Zhuoran Yin, Neta Rosenzweig, Kilian Kleemann, Xiaoming Zhang, Wesley N Brandao, Milica Margeta, Caitlin M Schroeder, Sebastian Silveira, Christian Gauthier, Dania Mallah, Kristen Pitts, Ana Durao, Shawn Herron, Hannah Shorey, Yiran Cheng, Jen‐Li Barry, Sam Wakelin, Jared Rhee, Anthony Yung, Michael Aronchik, Chao Wang, Nimansha Jain, Xin Bao, Emma Gerrits, Nieske Brouwer, Amy Deik, Daniel G. Tenen, Tsuneya Ikezu, Nicolas G. Santander, Gabriel L. McKinsey, Caroline Baufeld, Dean Sheppard, Susanne Krasemann, Bart Eggen, Clary Clish, Rudolph E. Tanzi, Charlotte Madore, Thomas D. Arnold, David M. Holtzman
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



APOE ε4 is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD).


Generation of CX3CR1‐CREERT2 mice crossed to APOE‐KI(E3 and E4)fl/fl: APP/PS1 and APOE‐KI(E3 and E4)fl/fl: P301S mice. Microglia and astrocytes were isolated and sequenced using either bulk RNA‐seq (MGnD‐Paradigm) or single‐cell RNA‐seq. Crosstalk between cells was determined using the NichenetR database and validated using 1) recombinant Lgals3 intracranial injection into APP/PS1 mice and 2) adoptive transfer of microglia, from APOE3‐KI, APOE4‐KI, and APOE4‐cKO mice challenged with labeled apoptotic neurons, into WT mice and isolation of astrocytes. Validation in the brain of AD donors carrying the APOE e3/3 and e3/4 alleles.


Here we show, in mice and in humans, a negative role of microglial APOE4 in the induction of MGnD response to neurodegeneration. Deletion of microglial APOE4 restores MGnD phenotype, associated with neuroprotection in P301S tau transgenic mice, and decreases pathology in APP/PS1 mice. MGnD‐astrocyte crosstalk associated with b‐amyloid (Ab) plaque encapsulation and clearance is mediated via Lgals3 signaling following microglial APOE4 deletion. In the brain of AD donors carrying the APOE ε4 allele, we found a sex‐dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, as compared to APOE ε3/3 carriers. Mechanistically, APOE4‐mediated induction of ITGB8‐TGFb signaling impairs MGnD response via upregulation of TGFb‐mediated microglial homeostatic checkpoints, including INPP5D. Microglial deletion of Inpp5d restores MGnD‐astrocyte crosstalk and facilitates plaque clearance in APP/PS1 mice. Genetic and pharmacological blocking of ITGB8‐TGFb signaling enhanced MGnD response associated with increased plaque clearance in AD mice.


We identify the microglial APOE4‐ITGB8‐TGFb pathway as a negative regulator of microglia‐astrocyte response to AD pathology, and restoring MGnD phenotype via blocking ITGB8‐TGFb signaling may provide new molecular targets to modulate and restore functional microglia in AD.

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