Mesencephalic astrocyte-derived neurotrophic factor (MANF) protects against Aβ toxicity via attenuating Aβ-induced endoplasmic reticulum stress
Date
2019Journal
Journal of NeuroinflammationPublisher
BioMed Central Ltd.Type
Article
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Background: Extracellular accumulation of amyloid β-peptide (Aβ) is one of pathological hallmarks of Alzheimer's disease (AD) and contributes to the neuronal loss. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress-inducible neurotrophic factor. Many groups, including ours, have proved that MANF rescues neuronal loss in several neurological disorders, such as Parkinson's disease and cerebral ischemia. However, whether MANF exerts its protective effect against Aβ neurotoxicity in AD remains unknown. Methods: In the present study, the characteristic expressions of MANF in Aβ1–42-treated neuronal cells as well as in the brains of APP/PS1 transgenic mice were analyzed by immunofluorescence staining, qPCR, and Western blot. The effects of MANF overexpression, MANF knockdown, or recombination human MANF protein (rhMANF) on neuron viability, apoptosis, and the expression of ER stress-related proteins following Aβ1-42 exposure were also investigated. Results: The results showed the increased expressions of MANF, as well as ER stress markers immunoglobulin-binding protein (BiP) and C/EBP homologous protein (CHOP), in the brains of the APP/PS1 transgenic mice and Aβ1-42 -treated neuronal cells. MANF overexpression or rhMANF treatment partially protected against Aβ1-42 -induced neuronal cell death, associated with marked decrease of cleaved caspase-3, whereas MANF knockdown with siRNA aggravated Aβ1-42 cytotoxicity including caspase-3 activation. Further study demonstrated that the expressions of BiP, ATF6, phosphorylated-IRE1, XBP1s, phosphorylated-eIF2α, ATF4, and CHOP were significantly downregulated by MANF overexpression or rhMANF treatment in neuronal cells following Aβ1–42 exposure, whereas knockdown of MANF has the opposite effect. Conclusions: These findings demonstrate that MANF may exert neuroprotective effects against Aβ-induced neurotoxicity through attenuating ER stress, suggesting that an applicability of MANF as a therapeutic candidate for AD. © 2019 The Author(s).Sponsors
This work was supported by the National Natural Science Foundation of China (81372576, 81673438 to SYX, 81302755 to FLJ), State's Key Project of Research and Development Plan (YFC1305902 to SYX), and Key projects of Anhui provincial natural science research in colleges and universities (KJ2017A167 to FLJ).Identifier to cite or link to this item
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85061496708&doi=10.1186%2fs12974-019-1429-0&partnerID=40&md5=fc14d98a755153fbc6a3ea9b24ccef0f; http://hdl.handle.net/10713/8676ae974a485f413a2113503eed53cd6c53
10.1186/s12974-019-1429-0
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