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

Authors:
Oleg Butovsky, Zhuoran Yin, Neta Rosenzweig, Kilian Kleemann, Wesley Brandão, Milica Margeta, Jen-Li Barry, Michael Aronchik, Dean Sheppard, Bart Eggen, Rudolph Tanzi, Charlotte Madore, Thomas Arnold, David Holtzman

Organisations:
Harvard Medical School, United States of America

Presenting author:
Oleg Butovsky

Exposition date:
Saturday, September 16, 2023

Exposition position:
097/2

Background

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).

Methods

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-astrocyte crosstalk was determined using scRNAseq and NichenetR database and validated in the brain of AD donors carrying the APOE e3/3 and e3/4 alleles.

Results

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 β-amyloid (Aβ) plaque encapsulation and clearance are mediated via Lgals3 signaling following microglial APOE4deletion. 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 TGFβ-mediated microglial homeostatic checkpoints, including INPP5D. Microglial deletion of Inpp5drestores MGnD-astrocyte crosstalk and facilitates plaque clearance in APP/PS1 mice. Genetic and pharmacological blocking of ITGB8-TGFβ signaling enhanced MGnD response associated with increased plaque clearance in AD mice.

Conclusions

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