Impacts of Acute Hypoxia on Alzheimer's Disease-Like Pathologies in APPswe/PS1dE9 Mice and Their Wild Type Littermates.

Feng Zhang,Cheng Cheng,Rujia Zhong,Song Li,Hongqian Qi,Weidong Le,Xinyao Liu,Yufei Liu

doi:10.3389/fnins.2018.00314

Abstract

Alzheimer's disease (AD) is the most common form of dementia and pathologically featured by β-amyloid (Aβ) plaque deposition and hyper-phosphorylated tau aggregation in the brain. Environmental factors are believed to contribute to the pathogenesis and progression of AD. In the present study, we investigated the impacts of acute hypoxia on Aβ and tau pathologies, neuroinflammation, mitochondrial function, and autophagy in APPswe/PS1dE9 AD mouse model. Male APPswe/PS1dE9 transgenic (Tg) mice and their age-matched wild type (Wt) littermates were exposed to one single acute hypoxic episode (oxygen 7%) for 24 h. We found that acute hypoxia exposure increased the expressions of amyloid precursor protein (APP), anterior pharynx-defective 1 (APH1) and cyclin-dependent kinase 5 (CDK5), and promoted tau phosphorylation at T181 and T231 residues in both Tg and Wt mice. In addition, acute hypoxia also induced autophagy through the mammalian target of rapamycin (mTOR) signaling, elicited abnormal mitochondrial function and neuroinflammation in both Tg and Wt mice. In summary, all these findings suggest that acute hypoxia could induce the AD-like pathological damages in the brain of APPswe/PS1dE9 mice and Wt mice to some extent.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia and pathologically featured by amyloid β (Aβ) deposition and hyper-phosphorylated tau aggregation in the brain
We found that the pro-inflammatory M1 marker cluster of differentiation 86 (CD86), along with pro-inflammatory cytokines and chemokines, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), chemokine C-C motif ligand 2 (CCL2) and CCL3, were increased in both hippocampus and cortex in hypoxic mice compared to normoxic mice
We demonstrated the impacts of acute hypoxia on AD-like pathologies including Aβ and tau pathologies, dysregulated autophagy, mitochondrial dysfunction and neuroinflammation

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia and pathologically featured by amyloid β (Aβ) deposition and hyper-phosphorylated tau aggregation in the brain. Tau is a microtubule associated protein which binds to microtubules and stabilizes their structure (Giacobini and Gold, 2013). Hyper-phosphorylation of tau is caused by an imbalanced regulation of kinases and phosphatases, including glycogen synthase kinase-3β (GSK-3β), cyclin-dependent-like kinase-5 (CDK5) and protein phosphatase 2A (PP2A) (Sontag et al, 2007; Iqbal et al, 2016). Hyper-phosphorylated tau is unable to interact with microtubules and results in disruption of axonal flow. The hyper-phosphorylated tau promotes its self-assembly into paired helical filaments (PHFs), which aggregates into neurofibrillary tangles (NFTs) (Giacobini and Gold, 2013)

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