Related Experiment Video
Updated: Jan 29, 2026
Visualization of Endoplasmic Reticulum Subdomains in Cultured Cells
Published on: February 18, 2014
Mesencephalic astrocyte-derived neurotrophic factor (MANF) protects against Aβ toxicity via attenuating Aβ-induced
Shengchun Xu1, Zemin Di1,2,3, Yufeng He1,2,3
1School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.
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.
Insights
Mesencephalic astrocyte-derived neurotrophic factor (MANF) shows neuroprotective effects against amyloid-beta (Aβ) toxicity in Alzheimer's disease models. MANF attenuates endoplasmic reticulum (ER) stress, suggesting its potential as a therapeutic for AD.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Amyloid-beta (Aβ) peptide accumulation is a hallmark of Alzheimer's disease (AD), leading to neuronal loss.
- Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress-inducible neurotrophic factor known to protect neurons in other neurological disorders.
- The neuroprotective role of MANF against Aβ toxicity in AD has not been previously established.
Purpose of the Study:
- To investigate the role of MANF in protecting against Aβ-induced neurotoxicity in Alzheimer's disease.
- To analyze MANF expression in AD models and its effect on ER stress pathways.
Main Methods:
- Analysis of MANF and ER stress marker expression in Aβ-treated neuronal cells and APP/PS1 transgenic mouse brains using immunofluorescence, qPCR, and Western blot.
- Investigating the impact of MANF overexpression, knockdown, and recombinant human MANF protein (rhMANF) on neuronal viability, apoptosis, and ER stress markers.
Main Results:
- Increased MANF and ER stress markers (BiP, CHOP) were observed in AD models and Aβ-treated cells.
- MANF overexpression or rhMANF treatment protected against Aβ-induced neuronal death and caspase-3 activation.
- MANF modulated key ER stress pathway components, including BiP, ATF6, IRE1, XBP1s, eIF2α, ATF4, and CHOP, mitigating Aβ-induced ER stress.
Conclusions:
- MANF exhibits neuroprotective effects against Aβ-induced neurotoxicity in Alzheimer's disease.
- MANF exerts its protective effects by attenuating endoplasmic reticulum stress.
- MANF represents a potential therapeutic candidate for Alzheimer's disease.
Related Concept Videos
01:39Endoplasmic Reticulum
01:43The Endoplasmic Reticulum
01:21Smooth Endoplasmic Reticulum
The ER provides optimal conditions for synthesizing steroid hormones and lipids, such as phospholipids and triglycerides. Traditionally, lipid metabolism was considered to be a smooth ER function. However, there is no direct evidence to prove that rough ER is completely excluded from lipid...
01:34Directing Proteins to the Rough Endoplasmic Reticulum
02:02Responses to Salt Stress
02:42Transcription Attenuation in Prokaryotes
There are several different mechanisms used to attenuate transcription. In ribosome mediated...