Improving effects of melatonin on memory and synaptic potentiation in a mouse model of Alzheimer's-like disease: the involvement of glutamate homeostasis and mGluRs receptors.
Study Goal
The researchers aimed to investigate melatonin's therapeutic potential in modulating glutamate signaling and mGluR activity to improve memory and synaptic plasticity in an Alzheimer's-like mouse model.
Results Summary
Melatonin improved cognitive function, restored mGluR expression, reduced tau hyperphosphorylation, and enhanced synaptic plasticity, with early intervention showing superior outcomes.
Population
C57BL/6 mice with induced Alzheimer's-like pathology.
Effective Dosage
10 mg/kg, administered intraperitoneally.
Duration
Early intervention (2 weeks post-induction) and late intervention (4 weeks post-induction).
Interactions
None mentioned
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
melatonin (10 mg/kg) | increase | cognitive function | AD-like mouse model (C57BL/6 mice) | - | improved | #1 |
melatonin (10 mg/kg) | decrease | neuronal loss | AD-like mouse model (C57BL/6 mice) | - | reduced | #2 |
melatonin (10 mg/kg) | increase | myelin integrity | AD-like mouse model (C57BL/6 mice) | - | improved | #3 |
melatonin (10 mg/kg) | decrease | tau hyperphosphorylation | AD-like mouse model (C57BL/6 mice) | - | decreased | #4 |
melatonin (10 mg/kg) | increase | mGluR expression | AD-like mouse model (C57BL/6 mice) | - | restored | #5 |
melatonin (10 mg/kg) | decrease | GSK3 activity | AD-like mouse model (C57BL/6 mice) | - | reduced | #6 |
melatonin (10 mg/kg) (early intervention) | increase | cognitive function | AD-like mouse model (C57BL/6 mice) | - | yielded superior outcomes | #7 |
melatonin (10 mg/kg) (early intervention) | increase | synaptic plasticity | AD-like mouse model (C57BL/6 mice) | - | partial restoration | #8 |
intra-hippocampal injection of cis-phospho tau | decrease | memory deficits | C57BL/6 mice | - | displayed | #9 |
intra-hippocampal injection of cis-phospho tau | decrease | synaptic dysfunction | C57BL/6 mice | - | displayed | #10 |
BACKGROUND: Alzheimer's disease (AD) is characterized by progressive cognitive decline and synaptic dysfunction, largely driven by amyloid plaques and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. These pathological hallmarks disrupt glutamate signaling, which is essential for synaptic plasticity and memory consolidation. This study investigates the therapeutic potential of melatonin on memory and synaptic plasticity in an AD-like mouse model, with a focus on its regulatory effects on glutamate homeostasis and metabotropic glutamate receptors (mGluRs). METHODS: The study began with an in-silico bioinformatics analysis of RNA-seq datasets from hippocampal tissues of AD patients to identify differentially expressed genes (DEGs) related to glutamate signaling and tau pathology. An AD-like model was induced via intra-hippocampal injection of cis-phospho tau in C57BL/6 mice. Memory function was assessed using behavioral tests. Synaptic plasticity was evaluated using in vitro field potential recording of hippocampal slices. Histological analyses included Nissl staining for neuronal density, Luxol Fast Blue for myelin integrity, and immunofluorescence for tau hyperphosphorylation. Molecular studies employed qPCR and Western blot to assess glutamate-related markers and tau phosphorylation. Melatonin (10 mg/kg) was administered intraperitoneally, starting either two weeks (early intervention) or four weeks (late intervention) post-induction. RESULTS: Key molecular targets in glutamate signaling pathways were identified using bioinformatics. AD-like mice displayed memory deficits and synaptic dysfunction. Melatonin improved cognitive function, especially with early intervention, as confirmed by behavioral tests. Histological studies revealed reduced neuronal loss, improved myelin integrity, and decreased tau hyperphosphorylation. Molecular findings showed restored mGluR expression and reduced GSK3 activity. Early intervention yielded superior outcomes, with partial restoration of synaptic plasticity observed in LTP recordings. CONCLUSIONS: These findings underscore the neuroprotective properties of melatonin, mediated by its ability to modulate glutamate signaling and mGluR activity, offering new insights into its potential as a therapeutic agent for AD. Additionally, the results suggest that earlier administration of melatonin may significantly enhance its efficacy, highlighting the importance of timely intervention in neurodegenerative diseases.