Neuromodulatory action of picomolar extracellular Aβ42 oligomers on pre- and postsynaptic mechanisms underlying synaptic function and memory.

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.