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Hippocampal proteomic alteration in triple transgenic mouse model of Alzheimer’s disease: insights into the role of PINK 1 proteins in donepezil treatment Hippocampal proteomic alteration in triple transgenic mouse model of Alzheimer’s disease: insights into the role of PINK 1 proteins in donepezil treatment

ABSTRACT: Donepezil, an acetylcholinesterase (AChE) inhibitor, was approved by FDA for the symptomatic therapies of patients with Alzheimer’s disease (AD) in 1996. Although donepezil have been regarded as the standard and first-line treatment for AD, the capacity of such drugs to alter the underlying disease process is still unclear. In this study, we sought to explore the possible protective mechanism of donepezil in triple-transgenic Alzheimer’s disease (3×Tg-AD) mice model. 3×Tg-AD mice were treated for 4 months with donepezil (1.3 mg /kg) and its effects were evaluated by behavioral tests and molecular analysis. The cognition of donepezil-treated mice was restored significantly. Reduced levels of soluble and insoluble amyloid beta 1-40 (Aβ 1-40) and amyloid beta 1-42 (Aβ 1-42) as well as senile plaques were observed. Moreover, donepezil treatment prevented the dendritic spine loss in hippocampus neurons. We further investigated the effects of donepezil on the hippocampal protein of 3×Tg-AD mice by quantitative proteomics technology. Proteomic results indicated that donepezil significantly elevated the levels of PINK1, NFASC, MYLK2, and RASN in the hippocampus, and modulated axon guidance, mitophagy, mTOR signaling, and MAPK pathway. The results suggested that donepezil induced neuroprotective effects through multiple mechanisms.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, Hippocampal Neuron, Neutrophil

DISEASE(S): Alzheimer's Disease

SUBMITTER: xinhua zhou

LAB HEAD: Xinhua Zhou

PROVIDER: PXD010604 | Pride | 2018-12-03

REPOSITORIES: Pride

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			Action	DRS
	CDCTMTH1-120180124.wiff	Wiff
	CDCTMTH1-120180124.wiff.1.idx2	Wiff
	CDCTMTH1-120180124.wiff.scan	Wiff
	CDCTMTH1-220180124.wiff	Wiff
	CDCTMTH1-220180124.wiff.1.idx2	Wiff

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Hippocampal Proteomic Alteration in Triple Transgenic Mouse Model of Alzheimer's Disease and Implication of PINK 1 Regulation in Donepezil Treatment.

Zhou Xinhua X Xiao Wei W Su Zhiyang Z Cheng Jiehong J Zheng Chengyou C Zhang Zaijun Z Wang Yuqiang Y Wang Liang L Xu Benhong B Li Shupen S Yang Xifei X Pui Man Hoi Maggie M

Journal of proteome research 20181207 4

Donepezil is a clinically approved acetylcholinesterase inhibitor (AChEI) for cognitive improvement in Alzheimer's disease (AD). Donepezil has been used as a first-line agent for the symptomatic treatment of AD, but its ability to modify disease pathology and underlying mechanisms is not clear. We investigated the protective effects and underlying mechanisms of donepezil in AD-related triple transgenic (APPSwe/PSEN1M146V/MAPTP301L) mouse model (3×Tg-AD). Mice (8- ...[more]

PMID: 30484658

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Project description:The pathophysiology of Alzheimer’s disease (AD) is multifactorial with characteristic extracellular accumulation of amyloid-beta (Aβ) and intraneuronal aggregation of hyperphosphorylated tau in the brain. Development of disease-modifying treatment for AD has been challenging. Recent studies suggest that deleterious alterations in neurovascular cells happens in parallel with Aβ accumulation, inducing tau pathology and necroptosis. Therefore, therapies targeting cellular Aβ and tau pathologies may provide a more effective strategy of disease intervention. Tetramethylpyrazine nitrone (TBN) is a nitrone derivative of tetramethylpyrazine, an active ingredient from Ligusticum wallichii Franchat (Chuanxiong). We previously showed that TBN is a potent scavenger of free radicals with multi-targeted neuroprotective effects in rat and monkey models of ischemic stroke. The present study aimed to investigate the anti-AD properties of TBN. We employed AD-related cellular model (N2a/APPswe) and transgenic mouse model (3×Tg-AD mouse) for mechanistic and behavioral studies. Our results showed that TBN markedly improved cognitive functions and reduced Aβ and hyperphosphorylated tau levels in mouse model. Further investigation of the underlying mechanisms revealed that TBN promoted non amyloidogenic processing pathway of amyloid precursor protein (APP) in N2a/APPswe in vitro. Moreover, TBN preserved synapses from dendritic spine loss and upregulated synaptic protein expressions in 3×Tg-AD mice. Proteomic analysis of 3×Tg-AD mouse hippocampal and cortical tissues showed that TBN induced neuroprotective effects through modulating mitophagy, MAPK and mTOR pathways. In particular, TBN significantly upregulated PINK1, a key protein for mitochondrial homeostasis, implicating PINK1 as a potential therapeutic target for AD. In summary, TBN improved cognitive functions in AD-related mouse model, inhibited Aβ production and tau hyperphosphorylation, and rescued synaptic loss and neuronal damage. Multiple mechanisms underlie the anti-AD effects of TBN including the modulation of APP processing, mTOR signaling and PINK1-related mitophagy.

Project description:INTRODUCTION Alzheimer’s disease (AD) is an advanced neurodegenerative disorder characterized by progressive impairment in both memory loss and cognitive capacities, which resulting in severe dementia [1]. The pathogenesis of AD is complicated and poorly understood. According to the World Alzheimer Report 2018, it is estimated that AD affects at least 50 million persons throughout the world, and the number of people with AD will double nearly every 20 years [2]. Over the past decade, various theories have been developed for the neuropathological level of AD, but the most popular distinct pathological hallmarks is extracellular accumulation of amyloid beta (Aβ) plaques, as well as the neurofibrillary tangles (NFTs) composed of the hyperphosphorylated tau in the form of in the select brain regions [3]. The other factors including mitochondrial dysfunction, oxidative stress, brain inflammation and neurotransmitter disturbances pathology have been recognized as a contributing factor in the pathogenesis of AD [4]. To date, only symptomatic therapies are available for AD patients. Cholinesterase inhibitors (CIs) are approved for mild to moderate AD patients, and memantine is the only one N-methyl-D-aspartate receptor (NMDAR) antagonist has been approved for moderate to severe AD [5]. NMDAR is a glutamate ionotropic receptor, they display high Ca2+ permeability and voltage-dependent block by Mg2+[6]. In AD patients, NMDARs could be overactivated due to increasing glutamate release from presynaptic neurons. Overactived NMDARs lead first to Ca2+ overload in postsynaptic neurons, followed by desensitization and internalization, resulting in synaptic dysfunction and ultimately cell death [7, 8]. The numerous factors than can influence the levels of endogenous glutamate release in the pathogenesis of AD, deposition of Aβplaques, soluble Aβoligomers, NFTs, mitochondrial dysfunction and oxidative stress have been associated with the higher concentration of glutamate release[9, 10]. Memantine is an uncompetitive, moderate affinity NMDA receptor (NMDAR) antagonist which is used for a further therapeutic option of moderate to severe AD [5]. Its effects have been investigated in a large number of in vitro and in vivo studies, which indicated that memantine can against Aβ-induced glutamate-mediated toxicity, attenuate phosphorylation of tau and reduces level of total precursor protein (APP) in human neuroblastoma SK-N-SH cells [11], and lower Aβ1-42 secretion and plaques in primary cortical neuronal culture cells [9, 12]. Some studies showed that memantine also completely protected against Aβ-induced ROS injure in the primary hippocampal neurons [13]. Studies with transgenic animal models showed that memantine reduced the levels of soluble Aβ1-42, Aβ plaque deposition and lowered the loss of synaptic density in APP/PS1mice [4, 14, 15], and decreased the levels of total tau and hyperphosphorylated tau in 3×Tg-AD mice [3]. Furthermore, memantine altered genes expression in adult rat brain [16], and modulated protein profiles in Down syndrome mice brain [17]. However, no comprehensive study of proteomic characteristics description of 3×Tg-AD transgenic mice under the memantine treatment has been conducted to date as far as we searched. In order to better understand the multiple actions of memantine, we conducted detailed analysis of proteomics and bioinformatics to dissect the molecular mechanisms of memantine for the treatment of AD.

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Hippocampal Proteomic Alteration in Triple Transgenic Mouse Model of Alzheimer's Disease and Implication of PINK 1 Regulation in Donepezil Treatment.

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