Presenilin 1 phosphorylation regulates amyloid-\u03b2 degradation by microglia

Jose Henrique Ledo,Paul Greengard,Ran Zhang,Estefania P Azevedo,Eitan Wong,Olga G Troyanskaya,Victor Bustos,Jerry C Chang,Thomas Liebmann,Hernandez Moura Silva

doi:10.1038/s41380-020-0856-8

Abstract

Amyloid-β peptide (Aβ) accumulation in the brain is a hallmark of Alzheimer’s Disease. An important mechanism of Aβ clearance in the brain is uptake and degradation by microglia. Presenilin 1 (PS1) is the catalytic subunit of γ-secretase, an enzyme complex responsible for the maturation of multiple substrates, such as Aβ. Although PS1 has been extensively studied in neurons, the role of PS1 in microglia is incompletely understood. Here we report that microglia containing phospho-deficient mutant PS1 display a slower kinetic response to micro injury in the brain in vivo and the inability to degrade Aβ oligomers due to a phagolysosome dysfunction. An Alzheimer’s mouse model containing phospho-deficient PS1 show severe Aβ accumulation in microglia as well as the postsynaptic protein PSD95. Our results demonstrate a novel mechanism by which PS1 modulates microglial function and contributes to Alzheimer’s -associated phenotypes.

Highlights

Microglia are yolk sac–derived innate immune cells in the brain that play key roles in multiple stages of Alzheimer’s disease (AD), from inflammatory responses and synapse pruning to degradation of amyloid-β (Aβ) peptide, all of Supplementary information The online version of this article contains supplementary material, which is available to authorized users.which are thought to drive AD pathology progression [1, 2]
The present study adds an additional mechanism to our previous findings in neurons, we show that Presenilin 1 (PS1) phosphorylation at serine 367 plays an important role in regulating Aβ levels by microglia
We found that the number of microglia associated with the enveloping of plaques in 5xFAD * Psen1KI/KI mice is comparable to 5xFAD mice (Fig. 4h), suggesting that the increase in Aβ in 5xFAD * Psen1KI/KI mice was not due to reduced number of microglia interacting with Aβ plaques

Summary

Introduction

In early stages of AD, microglia actively internalize different assemblies of Aβ and eliminate them through endolysosomal degradation [3,4,5]. Aβ clearance by microglia may be inhibited in late AD due to accumulation of plaques. TREM2 facilitates Aβ phagocytosis by microglia [10] and CD33 impairs microglia-mediated Aβ clearance [8]. The mechanisms by which microglial cells become defective in AD is incompletely understood

Methods

Results

Conclusion