Alzheimer\u2019s disease pathological lesions activate the spleen tyrosine kinase

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

doi:10.1186/s40478-017-0472-2

Jonas Elias Schweig, David Beaulieu-Abdelahad + Show 6 more

Open Access

https://doi.org/10.1186/s40478-017-0472-2

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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.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disease that accounts for the majority of all cases of dementia
spleen tyrosine kinase (Syk) activation in activated microglia and non-glial cells associated with Aβ-plaques in Tg APPsw and Tg PS1/ APPsw mice To investigate whether pathological Syk activation occurs in the brain of AD mouse models, we analyzed the brains of 116-week-old wild-type, Tg APPsw and Tg PS1/APPsw mice using high-resolution confocal microscopy and immunofluorescence
We observed that pSyk immunoreactivity is upregulated near Aβ plaques but neither colocalizes with microglia nor astrocytes suggesting that it could be of neuronal origin. (Fig. 1e)

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease that accounts for the majority of all cases of dementia. AD pathological hallmarks include extracellular aggregates of Aβ, intracellular tau hyperphosphorylation and aggregation, as well as neuroinflammation. Tau is a microtubule-associated protein (MAP) involved in many essential cellular processes including stabilization of the microtubule network, thereby providing a functional basis for intracellular transport [10]. Misfolding and pathological post-translational modifications including tau. Through cleavage of the amyloid precursor protein (APP) by α, β and γ-secretases different variants of Aβ and soluble APP forms (α, β) are generated [41]. A variety of posttranslational modifications and the nature of the Aβ variants define their susceptibility to aggregation and neurotoxicity [41, 42]. Several mutations in the APP and presenilin (PSEN1/2) genes

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