Melatonin protective effect against amyloid β-induced neurotoxicity mediated by mitochondrial biogenesis; involvement of hippocampal Sirtuin-1 signaling pathway
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Updated: Jan 29, 2026
Preparation of Oligomeric β-amyloid1-42 and Induction of Synaptic Plasticity Impairment on Hippocampal Slices
Published on: July 14, 2010
Mitra Ansari Dezfouli1, Maryam Zahmatkesh2, Maryam Farahmandfar1
1Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Abstract:
Melatonin has a potential therapeutic value in Alzheimer's disease (AD), a disease that is associated with a dramatic decline in memory and cognitive abilities. The aggregation of the amyloid β (Aβ) peptide, a hallmark of AD, deactivates mitochondrial biogenesis and antioxidant defenses. Melatonin as an endogenous antioxidant, decreases in plasma and cerebrospinal fluid of AD patients. Even though several experimental studies have demonstrated the melatonin neuroprotection in AD, clinical trials of melatonin therapy have not yet confirmed outstanding results in AD patients. Better understanding of the molecular mechanisms involved in melatonin neuroprotective effects may pave the way for an efficient therapy. Hence, we investigated the involvement of silent information regulator 1 (SIRT1) signaling and mitochondrial biogenesis in melatonin neuroprotection in a rat model of cognitive impairment induced by intra-hippocampal Aβ injection. Animals assigned to melatonin treatment in the presence or absence of SIRT1 inhibitor (EX527), for 14 consecutive days. Spatial working memory and anxiety level were examined with Y-maze and elevated plus maze tests respectively. Hippocampal SIRT1, transcription factor-A mitochondrial (TFAM) and mitochondrial DNA (mtDNA) copy number were measured. We observed a decrease in hippocampal SIRT1, which accompanied with reduction in TFAM and mtDNA copy number in the Aβ-injected rats. Melatonin treatment increased hippocampal SIRT1 and TFAM expression and enhanced mtDNA copy number in the hippocampus. It also improved memory, ameliorated the anxiety, and attenuated hippocampal cell damage in the Aβ-injected animals. These effects were blocked by EX527 administration, suggesting SIRT1 signaling involvement in melatonin neuroprotective effect. This mechanism may introduce a new promising strategy in battle against AD.
Insights
Melatonin may help Alzheimer's disease (AD) by boosting SIRT1 signaling and mitochondrial function, improving memory and reducing anxiety in rats. These neuroprotective effects were confirmed through SIRT1 activation, offering a potential new strategy for AD therapy.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Alzheimer's disease (AD) involves amyloid-beta (Aβ) peptide aggregation, mitochondrial dysfunction, and reduced antioxidant defenses.
- Melatonin, an endogenous antioxidant, decreases in AD patients, suggesting a potential therapeutic role.
- Existing clinical trials for melatonin in AD have yielded inconclusive results, necessitating further investigation into its mechanisms.
Purpose of the Study:
- To investigate the role of silent information regulator 1 (SIRT1) signaling and mitochondrial biogenesis in melatonin's neuroprotective effects in a rat model of AD.
- To determine if melatonin can restore SIRT1, mitochondrial transcription factor A (TFAM), and mitochondrial DNA (mtDNA) levels in the hippocampus.
- To assess the impact of melatonin on cognitive function and anxiety in Aβ-induced cognitive impairment.
Main Methods:
- A rat model of cognitive impairment was established by intra-hippocampal injection of Aβ.
- Rats received melatonin treatment, with or without the SIRT1 inhibitor EX527, for 14 days.
- Spatial working memory, anxiety levels, and hippocampal levels of SIRT1, TFAM, and mtDNA copy number were assessed.
Main Results:
- Aβ injection led to decreased hippocampal SIRT1, TFAM, and mtDNA copy number.
- Melatonin treatment increased hippocampal SIRT1 and TFAM expression and enhanced mtDNA copy number.
- Melatonin improved memory, reduced anxiety, and protected against hippocampal cell damage, effects which were reversed by EX527.
Conclusions:
- SIRT1 signaling and mitochondrial biogenesis are involved in melatonin's neuroprotective effects against Aβ-induced cognitive impairment.
- Melatonin shows promise as a therapeutic agent for Alzheimer's disease by targeting SIRT1 and mitochondrial pathways.
- Further research into this mechanism could lead to novel therapeutic strategies for combating Alzheimer's disease.
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