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

Failure of anti-amyloid-beta peptide (Aβ) therapies against Alzheimer9s 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, here we studied the pre- and post-synaptic mechanisms underlying the neuromodulatory action of picomolar amounts of oligomeric Aβ 42 (oAβ 42 ) on synaptic glutamatergic function in male and female mice. We found that pM oAβ 42 induces an increase of frequency of miniature excitatory postsynaptic currents and a decrease of paired pulse facilitation, associated with an increase in docked vesicle number, indicating that it augments neurotransmitter release at presynaptic level. oAβ 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 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 oAβ 42 . These effects were present upon extracellular but not intracellular application of the peptide, and involved α7 nicotinic acetylcholine receptors. These observations clarified the physiological role of oAβ 42 in synaptic function and memory formation providing solid fundamentals for investigating the pathological effects of high Aβ levels in the AD brains. SIGNIFICANCE STATEMENT High levels of oligomeric amyloid-beta 42 (oAβ 42 ) induce synaptic dysfunction leading to memory impairment in Alzheimer9s disease (AD). However, when at picomolar (pM) concentration, the peptide is needed to ensure long-term potentiation (LTP) and memory. Here we show that extracellular pM oAβ 42 increases neurotransmitter release, number of docked vesicles, postsynaptic density length, and expression of plasticity-related proteins leading to the conversion of early-LTP into late-LTP and of short-term into long-term memory. These effects require α7 nicotinic acetylcholine receptors and are mediated through the nitric oxide/cGMP/protein kinase G pathway. The knowledge of Aβ function in the healthy brain might be useful to understand the causes leading to its increase and detrimental effect in AD.