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Published on: October 17, 2015
Dysregulated APP expression and α-secretase processing of APP is involved in manganese-induced cognitive impairment
Yiping Yang1, Jie Zhang2, Xiaobo Yang3
1Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, Guangxi, China.
Abstract:
Excessive exposure to manganese (Mn) can cause cognitive impairment, a common feature of Alzheimer's disease (AD), but the mechanisms remain unclear. Amyloid precursor protein (APP) is key to AD pathogenesis, and whether APP and its secretase processing are involved in Mn-induced cognitive impairment remains unknown. In the present study, we established a model of Mn-induced neurotoxicity in vivo (male C57BL/6, 0-100 mg/kg Mn, 90 days, gastric gavage) and in vitro (Neuro-2a (N2a) cells, 0-800 μM Mn for 24 h; APP overexpression and APP shRNA N2a cells, 0 and 800 μM Mn for 24 h). We found impaired cognition of Mn-treated mice. Both in vivo and in vitro results consistently showed that Mn exposure inhibited the expression of APP, α-secretase, soluble APP alpha protein (sAPPα), and synapse proteins as well as the activity of α-secretase. However, Mn exposure showed no effect on the protein levels of β-secretase, Aβ40, and Aβ42 or the activity of β-secretase. Collectively, these findings demonstrate key roles of APP and its α-secretase processing in the regulation of Mn-induced cognitive impairment, which may act as a target for ameliorating Mn-induced neurotoxicity.
Insights
Manganese (Mn) exposure impairs cognition by reducing amyloid precursor protein (APP) and alpha-secretase activity, impacting synapse proteins. This suggests targeting APP processing may help treat Mn-induced neurotoxicity.
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Background:
- Excessive manganese (Mn) exposure is linked to cognitive impairment, resembling Alzheimer's disease (AD) symptoms.
- The precise mechanisms underlying Mn-induced cognitive deficits, particularly involving amyloid precursor protein (APP) processing, are not fully understood.
Purpose of the Study:
- To investigate the role of APP and its secretase processing in manganese-induced cognitive impairment.
- To elucidate the molecular mechanisms by which Mn exposure affects APP metabolism and synaptic function.
Main Methods:
- Established in vivo (mouse model) and in vitro (Neuro-2a cells) systems to study Mn neurotoxicity.
- Utilized APP overexpression and knockdown cell models to assess the impact of APP levels on Mn effects.
- Measured cognitive function, protein expression (APP, secretases, synapse proteins), and enzyme activities.
Main Results:
- Mn exposure impaired cognitive function in mice.
- Mn inhibited the expression and activity of APP and alpha-secretase, reducing soluble APP alpha protein (sAPPα) and synapse proteins.
- Mn did not affect beta-secretase activity or levels of Aβ40 and Aβ42.
Conclusions:
- APP and its alpha-secretase processing play a critical role in manganese-induced cognitive impairment.
- Targeting APP alpha-secretase pathway may offer a therapeutic strategy for mitigating Mn neurotoxicity and cognitive deficits.
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