Failure of anti-amyloid-β peptide (Aβ) 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 Aβ 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 Aβ42 (oAβ42) on synaptic glutamatergic function in male and female mice. We found that 200 pM oAβ42 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. oAβ42 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-calmodulin-dependent kinase II phosphorylated at Thr286, and brain-derived neurotrophic factor, suggesting a role for Aβ 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 oAβ42. These effects were present upon extracellular but not intracellular application of the peptide and involved +7 nicotinic acetylcholine receptors. These observations clarified the physiological role of oAβ42 in synaptic function and memory formation providing solid fundamentals for investigating the pathological effects of high Aβ levels in the AD brains.
|Titolo:||Neuromodulatory action of picomolar extracellular Aβ42 oligomers on presynaptic and postsynaptic mechanisms underlying synaptic function and memory|
PUZZO, DANIELA (Corresponding)
|Data di pubblicazione:||2019|
|Appare nelle tipologie:||1.1 Articolo in rivista|
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|Neuromodulatory action of picomolar extracellular Aβ42 oligomers.pdf||Versione Editoriale (PDF)||Open Access Visualizza/Apri|