Neuromodulatory action of picomolar extracellular A?42 oligomers on presynaptic and postsynaptic mechanisms underlying synaptic function and memory

Failure of anti-amyloid-? peptide (A?) 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? 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?42 (oA?42) on synaptic glutamatergic function in male and female mice. We found that 200 pM oA?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. oA?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-calmodulin-dependent kinase II phosphorylated at Thr286, and brain-derived neurotrophic factor, suggesting a role for A? 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?42. 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 oA?42 in synaptic function and memory formation providing solid fundamentals for investigating the pathological effects of high A? levels in the AD brains