Abstract
BackgroundExtracellular 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.MethodsIn 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.ResultsThe 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.ConclusionsThese 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.
Highlights
Extracellular accumulation of amyloid β-peptide (Aβ) is one of pathological hallmarks of Alzheimer’s disease (AD) and contributes to the neuronal loss
We showed the increased expressions of Mesencephalic astrocyte-derived neurotrophic factor (MANF) and endoplasmic reticulum (ER) stress markers binding protein (BiP) and C/EBP homologous protein (CHOP) in amyloid precursor protein (APP)/PS1 transgenic mice as well as in the neuronal cells treated with Aβ1–42, assessed the protective effect of MANF against Aβ neurotoxicity, and the underlying mechanism was investigated
These results suggest that Aβ1–42 decreased neuronal cell viability and induced cell apoptosis
Summary
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. Multiple studies showed that Aβ aggregation induces endoplasmic reticulum (ER) stress in neurons, which elicits the unfolded protein response (UPR) [8, 9]. If the provoking stress is prolonged, UPR can trigger the cell death program through the activation of C/EBP homologous protein (CHOP), a protein of the C/ EBP family of transcriptional regulators, known as growth arrest- and DNA damage-inducible gene 153 (GADD153) [12]. As neurons are highly susceptible to the toxic Aβ, ER stress-mediated cell death might have an important role in the pathogenesis of AD
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