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Ming-Chang Chiang1, Yi-Chuan Cheng2, Shiang-Jiuun Chen3
1Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City 242, Taiwan.
Abstract:
Alzheimer's disease (AD) is the general consequence of dementia and is diagnostic neuropathology by the cumulation of amyloid-beta (Aβ) protein aggregates, which are thought to promote mitochondrial dysfunction processes leading to neurodegeneration. AMP-activated protein kinase (AMPK), a critical regulator of energy homeostasis and a major player in lipid and glucose metabolism, is potentially implied in the mitochondrial deficiency of AD. Metformin, one of the widespread used anti- metabolic disease drugs, use its actions in part by stimulation of AMPK. While the mechanisms of AD are well established, the neuronal roles for AMPK in AD are still not well understood. In the present study, human neural stem cells (hNSCs) exposed to Aβ had significantly reduced cell viability, which correlated with decreased AMPK, neuroprotective genes (Bcl-2 and CREB) and mitochondria associated genes (PGC1α, NRF-1 and Tfam) expressions, as well as increased activation of caspase 3/9 activity and cytosolic cytochrome c. Co-treatment with metformin distinct abolished the Aβ-caused actions in hNSCs. Metformin also significantly rescued hNSCs from Aβ-mediated mitochondrial deficiency (lower D-loop level, mitochondrial mass, maximal respiratory function, COX activity, and mitochondrial membrane potential). Importantly, co-treatment with metformin significantly restored fragmented mitochondria to almost normal morphology in the hNSCs with Aβ. These findings extend our understanding of the central role of AMPK in Aβ-related neuronal impairment. Thus, a better understanding of AMPK might assist in both the recognition of its critical effects and the implementation of new therapeutic strategies in the treatment of AD.
Insights
Metformin protects human neural stem cells from amyloid-beta toxicity by restoring mitochondrial function and AMPK activity, offering potential Alzheimer's disease therapeutic strategies.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) aggregates, leading to mitochondrial dysfunction and neurodegeneration.
- AMP-activated protein kinase (AMPK) plays a role in energy homeostasis and is implicated in AD's mitochondrial deficiency.
- Metformin, an AMPK-stimulating drug, is widely used for metabolic diseases.
Purpose of the Study:
- To investigate the role of AMPK in Aβ-induced neuronal impairment in human neural stem cells (hNSCs).
- To evaluate the neuroprotective effects of metformin on Aβ-treated hNSCs.
Main Methods:
- Exposing hNSCs to Aβ and assessing cell viability, gene expression (AMPK, Bcl-2, CREB, PGC1α, NRF-1, Tfam), and apoptosis markers (caspase 3/9, cytochrome c).
- Evaluating mitochondrial function (D-loop, mass, respiratory function, COX activity, membrane potential) and morphology in Aβ-treated hNSCs.
- Assessing the effects of metformin co-treatment on these parameters.
Main Results:
- Aβ exposure reduced hNSC viability, decreased AMPK and neuroprotective gene expression, and increased apoptosis.
- Aβ induced mitochondrial dysfunction, including reduced D-loop levels, mass, respiratory function, COX activity, and membrane potential, alongside fragmented mitochondria.
- Metformin co-treatment abolished Aβ-induced toxicity, restored mitochondrial function and morphology, and normalized gene expression and apoptosis markers.
Conclusions:
- AMPK plays a critical role in mitigating Aβ-related neuronal damage.
- Metformin demonstrates significant neuroprotective effects against Aβ toxicity by enhancing AMPK activity and improving mitochondrial function.
- These findings highlight AMPK as a potential therapeutic target for Alzheimer's disease treatment.
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