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Preparation of Oligomeric β-amyloid1-42 and Induction of Synaptic Plasticity Impairment on Hippocampal Slices
Published on: July 14, 2010
Rapamycin protects against Aβ-induced synaptotoxicity by increasing presynaptic activity in hippocampal neurons
A E Ramírez1, C R Pacheco1, L G Aguayo1
1Department of Physiology, University of Concepción, P. O. Box 160-C, Concepcion, Chile.
Abstract:
The mammalian target of rapamycin (mTOR) is involved in the regulation of learning and memory. Recently, rapamycin has been shown to be neuroprotective in models for Alzheimer's disease in an autophagy-dependent manner. Here we show that rapamycin exerts neuroprotection via a novel mechanism that involves presynaptic activation. Rapamycin increases the frequency of miniature excitatory postsynaptic currents and calcium transients of rat hippocampal primary neurons by a mechanism that involves the up regulation of SV2, a presynaptic vesicular protein linked to neurotransmitter release. Under these conditions, rapamycin-treated hippocampal neurons are resistant to the synaptotoxic effect induced by Aβ oligomers, suggesting that enhancers of presynaptic activity can be therapeutic agents for Alzheimer's disease.
Insights
Rapamycin enhances learning and memory by activating presynaptic function, offering neuroprotection against Alzheimer's disease. This study reveals a novel mechanism involving increased neurotransmitter release and resistance to amyloid-beta toxicity.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- The mammalian target of rapamycin (mTOR) pathway regulates learning and memory.
- Rapamycin has demonstrated neuroprotective effects in Alzheimer's disease models, primarily through autophagy.
- A novel mechanism of rapamycin's neuroprotection involving presynaptic activation is investigated.
Purpose of the Study:
- To elucidate the mechanism by which rapamycin exerts neuroprotection in the context of Alzheimer's disease.
- To investigate the role of presynaptic activation in rapamycin-mediated neuroprotection.
- To determine if rapamycin can protect hippocampal neurons from amyloid-beta oligomer-induced synaptotoxicity.
Main Methods:
- Primary rat hippocampal neurons were cultured.
- The effects of rapamycin on miniature excitatory postsynaptic currents (mEPSCs) and intracellular calcium transients were measured.
- Expression levels of SV2, a presynaptic vesicular protein, were analyzed.
- Neurons were exposed to amyloid-beta (Aβ) oligomers to assess synaptotoxicity.
Main Results:
- Rapamycin treatment increased the frequency of mEPSCs and calcium transients in hippocampal neurons.
- This effect was associated with the upregulation of SV2, a protein crucial for neurotransmitter release.
- Rapamycin-treated neurons exhibited resistance to the synaptotoxic effects of Aβ oligomers.
Conclusions:
- Rapamycin confers neuroprotection through a novel mechanism involving presynaptic activation and enhanced neurotransmitter release.
- Upregulation of SV2 plays a key role in mediating rapamycin's beneficial effects.
- Enhancing presynaptic activity represents a potential therapeutic strategy for Alzheimer's disease.
