Dataset Information

Quantitative Proteomic Analysis Reveals potential roles of PRDX3 for neurite outgrowth in N2a-APPswe Cells

ABSTRACT: Alzheimer’s disease (AD) is characterized by amyloid plaques and neurofibrillary tangles accompanied with progressive neurite loss. Mitochondria play pivotal roles in Alzheimer’s disease development. PRDX3 is a mitochondrial peroxide reductase responsible for H2O2 scavenge and signaling transduction. In this study, we found knockdown PRDX3 in N2a-APPSwe cell line induced neurite outgrowth, but not reduced cell viability against tert-butyl hydroperoxide (TBHP) induced cell damage. We found knockdown of PRDX3 induced dysregulation of one hundred proteins by Tandem Mass Tag (TMT) labeled proteomic study. Gene Ontology analysis revealed that the dysregulated proteins are enriched on establishment of protein localization to plasma membrane, lipid catabolic process, and intermediate filament cytoskeleton organization. String analysis showed closely protein-protein interactions among the dysregulated proteins. Annexin A1 (ANXA1), serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PP2A) and glutathione S-transferase Mu 2 (GSTM2) were significantly upregulated in PRDX3 knockdown N2a-APPswe cell lines and verified by western blot. Our study for the first time revealed PRDX3 may also played important roles on neurite outgrowth and related AD development.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Benhong Xu

LAB HEAD: Benhong Xu

PROVIDER: PXD032733 | Pride | 2022-03-24

REPOSITORIES: Pride

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A quantitative proteomic analysis reveals the potential roles of PRDX3 in neurite outgrowth in N2a-APPswe cells.

Xu Benhong B Gao Chuanyue C Zhang Huan H Huang Xinfeng X Yang Xifei X Yang Chen C Liu Wei W Wu Desheng D Liu Jianjun J

Biochemical and biophysical research communications 20220305

Alzheimer's disease (AD) is characterized by amyloid plaques and neurofibrillary tangles accompanied by progressive neurite loss. Mitochondria play pivotal roles in AD development. PRDX3 is a mitochondrial peroxide reductase critical for H<sub>2</sub>O<sub>2</sub> scavenging and signal transduction. In this study, we found that PRDX3 knockdown (KD) in the N2a-APPswe cell line promoted retinoic acid (RA)-induced neurite outgrowth but did not reduce the viability of cells damaged by tert-butyl hyd ...[more]

PMID: 35303681

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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.

			Action	DRS
	_Mouse20210707_.fasta	Fasta
	n-a-app-.mzML	Mzml
	n-a-app-.mzid.gz	Mzid
	n-a-app-.pdResult	Other
	n-a-app-1.raw	Raw