Amyloid‐β impairs the phagocytosis of dystrophic synapses by astrocytes in Alzheimer's disease

Maria V Sanchez‐Mico,Cristina Nuñez‐Diaz,Elisabeth Sanchez‐Mejias,Antonia Gutierrez,Sebastian Jimenez,Clara Muñoz‐Castro,Marisa Vizuete,José C Davila,Javier Vitorica,Raquel Sanchez‐Varo,Angela Gomez‐Arboledas,Carmen Romero‐Molina,Victoria Navarro,Elena Galea

doi:10.1002/glia.23943

Abstract

Reactive astrocytes and dystrophic neurites, most aberrant presynaptic elements, are found surrounding amyloid-β plaques in Alzheimer's disease (AD). We have previously shown that reactive astrocytes enwrap, phagocytose, and degrade dystrophic synapses in the hippocampus of APP mice and AD patients, but affecting less than 7% of dystrophic neurites, suggesting reduced phagocytic capacity of astrocytes in AD. Here, we aimed to gain insight into the underlying mechanisms by analyzing the capacity of primary astrocyte cultures to phagocytose and degrade isolated synapses (synaptoneurosomes, SNs) from APP (containing dystrophic synapses and amyloid-β peptides), Tau (containing AT8- and AT100-positive phosphorylated Tau) and WT (controls) mice. We found highly reduced phagocytic and degradative capacity of SNs-APP, but not AT8/AT100-positive SNs-Tau, as compared with SNs-WT. The reduced astrocyte phagocytic capacity was verified in hippocampus from 12-month-old APP mice, since only 1.60 ± 3.81% of peri-plaque astrocytes presented phagocytic structures. This low phagocytic capacity did not depend on microglia-mediated astrocyte reactivity, because removal of microglia from the primary astrocyte cultures abrogated the expression of microglia-dependent genes in astrocytes, but did not affect the phagocytic impairment induced by oligomeric amyloid-β alone. Taken together, our data suggest that amyloid-β, but not hyperphosphorylated Tau, directly impairs the capacity of astrocytes to clear the pathological accumulation of oligomeric amyloid-β, as well as of peri-plaque dystrophic synapses containing amyloid-β, perhaps by reducing the expression of phagocytosis receptors such as Mertk and Megf10, thus increasing neuronal damage in AD. Therefore, the potentiation or recovery of astrocytic phagocytosis may be a novel therapeutic avenue in AD.

Highlights

We have examined the phagocytic capacity of astrocytes using synaptoneurosomes (SNs) isolated from amyloid precursor protein (APP) transgenic mice, which contain dystrophic synapses, compared to those isolated from WT and Tau (P301S) mice, which do not present dystrophic neurites
This inhibitory effect seems to be specific for Abeta-containing SNs, since other potentially toxic SNs, such as those derived from 9-month-old Tau-P301S mice containing total, AT8- and AT100-positive Tau, produced no alterations in SNs phagocytosis or degradation
Astrocytes become reactive around Abeta plaques in APP mice at 12 months of age, less than 2% of these reactive astrocytes present phagocytosed dystrophies in their cytoplasm

Summary

| INTRODUCTION

Alzheimer's disease (AD), the most common cause of dementia in the elderly, is pathologically characterized by the accumulation of extracellular amyloid-β (Abeta) plaques (Hane, Lee, & Leonenko, 2017; Masters et al, 1985), intraneuronal hyperphosphorylated Tau-laden neurofibrillary tangles (Laurent, Buée, & Blum, 2018; Spillantini & Goedert, 2013), synaptic loss and neuronal degeneration (Forner, Baglietto-Vargas, Martini, Trujillo-Estrada, & LaFerla, 2017; Hane et al, 2017), and presence of reactive microglia and astrocytes (Dansokho & Heneka, 2018; Heneka et al, 2015; Liu, Cui, Zhu, Kang, & Guo, 2014; Zhang & Jiang, 2015). Neuritic plaques are surrounded by reactive microglia and astrocytes (Heneka et al, 2015; Meyer-Luehmann et al, 2008; Serrano-Pozo, Betensky, Frosch, & Hyman, 2016), but it is not clear whether astrocytes promote the development and progression of dystrophies or whether, on the contrary, they constitute a physical barrier to limit their growth and protect other cells from the toxicity on the plaque halo, as suggested by several authors (Kraft et al, 2013; Perez-Nievas & Serrano-Pozo, 2018), and are engaged in the phagocytosis of dystrophies The latter scenario is supported by evidence that astrocytes can phagocytose Abeta (Jones, Minogue, Connor, & Lynch, 2013; Wyss-Coray et al, 2003; Xiao et al, 2014) and synapses (Chung et al, 2013; Chung, Allen, & Eroglu, 2015; Clarke & Barres, 2013), which may represent an attempt to protect other cells, such that alterations in the phagocytic capacity of astrocytes may result in reduced clearance of Abeta and dystrophic synapses. The maintenance of the phagocytic impairment after microglia depletion supports the conclusion that Abeta, and not microglia-released factors, is the factor limiting phagocytosis in astrocytes in AD

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION