期刊
JOURNAL OF NEUROSCIENCE
卷 39, 期 30, 页码 5986-6000出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0163-19.2019
关键词
amyloid precursor protein; amyloid-beta oligomers; neurotransmitter release; nicotinic receptors; synaptic plasticity; synaptic transmission
资金
- Alzheimer's Association [IIRG-09-134220, NIRG-14-321307]
- University of Catania (Bando Chance)
- Italian Ministry of University and Research [PRIN 2010-JFYFY2]
- INRCA IRCCS
- NIH [NS-049442, AG034248]
Failure of anti-amyloid-beta peptide (A beta) therapies against Alzheimer's disease (AD), a neurodegenerative disorder characterized by high amounts of the peptide in the brain, raised the question of the physiological role of A beta released at low concentrations in the healthy brain. To address this question, we studied the presynaptic and postsynaptic mechanisms underlying the neuromodulatory action of picomolar amounts of oligomeric A beta(42) (oA beta(42)) on synaptic glutamatergic function in male and female mice. We found that 200 pM oA beta(42) induces an increase of frequency of miniature EPSCs and a decrease of paired pulse facilitation, associated with an increase in docked vesicle number, indicating that it augments neurotransmitter release at presynaptic level. o beta 42 also produced postsynaptic changes as shown by an increased length of postsynaptic density, accompanied by an increased expression of plasticity-related proteins such as cAMP-responsive element binding protein phosphorylated at Ser133, calcium-cahnodulin-dependent kinase II phosphorylated at Thr286, and brain-derived neurotrophic factor, suggesting a role for An in synaptic tagging. These changes resulted in the conversion of early into late long-term potentiation through the nitric oxide/cGMP/protein kinase G intracellular cascade consistent with a cGMP-dependent switch from short- to long-term memory observed in vivo after intrahippocampal administration of picomolar amounts of oA beta(42). These effects were present upon extracellular but not intracellular application of the peptide and involved alpha 7 nicotinic acetylcholine receptors. These observations clarified the physiological role of oA beta(42) in synaptic function and memory formation providing solid fundamentals for investigating the pathological effects of high A beta levels in the AD brains.
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