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Open Access 01-12-2017 | Research

Alzheimer’s disease pathological lesions activate the spleen tyrosine kinase

Authors: Jonas Elias Schweig, Hailan Yao, David Beaulieu-Abdelahad, Ghania Ait-Ghezala, Benoit Mouzon, Fiona Crawford, Michael Mullan, Daniel Paris

Published in: Acta Neuropathologica Communications | Issue 1/2017

Abstract

The pathology of Alzheimer’s disease (AD) is characterized by dystrophic neurites (DNs) surrounding extracellular Aβ-plaques, microgliosis, astrogliosis, intraneuronal tau hyperphosphorylation and aggregation. We have previously shown that inhibition of the spleen tyrosine kinase (Syk) lowers Aβ production and tau hyperphosphorylation in vitro and in vivo. Here, we demonstrate that Aβ-overexpressing Tg PS1/APPsw, Tg APPsw mice, and tau overexpressing Tg Tau P301S mice exhibit a pathological activation of Syk compared to wild-type littermates. Syk activation is occurring in a subset of microglia and is age-dependently increased in Aβ-plaque-associated dystrophic neurites of Tg PS1/APPsw and Tg APPsw mice. In Tg Tau P301S mice, a pure model of tauopathy, activated Syk occurs in neurons that show an accumulation of misfolded and hyperphosphorylated tau in the cortex and hippocampus. Interestingly, the tau pathology is exacerbated in neurons that display high levels of Syk activation supporting a role of Syk in the formation of tau pathological species in vivo. Importantly, human AD brain sections show both pathological Syk activation in DNs around Aβ deposits and in neurons immunopositive for pathological tau species recapitulating the data obtained in transgenic mouse models of AD. Additionally, we show that Syk overexpression leads to increased tau accumulation and promotes tau hyperphosphorylation at multiple epitopes in human neuron-like SH-SY5Y cells, further supporting a role of Syk in the formation of tau pathogenic species. Collectively, our data show that Syk activation occurs following Aβ deposition and the formation of tau pathological species. Given that we have previously shown that Syk activation also promotes Aβ formation and tau hyperphosphorylation, our data suggest that AD pathological lesions may be self-propagating via a Syk dependent mechanism highlighting Syk as an attractive therapeutic target for the treatment of AD.

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Title: Alzheimer’s disease pathological lesions activate the spleen tyrosine kinase
Authors: Jonas Elias Schweig
Hailan Yao
David Beaulieu-Abdelahad
Ghania Ait-Ghezala
Benoit Mouzon
Fiona Crawford
Michael Mullan
Daniel Paris
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2017
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-017-0472-2

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Alzheimer’s disease pathological lesions activate the spleen tyrosine kinase

Abstract

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Abstract

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