ИСТИНА

Alzheimer's disease (AD) is the most common form of dementia resulting in cognitive function impairment. Soluble oligomeric β-amyloid peptide Aβ(1-42) is considered as the toxic form of β-amyloid peptides associated with cognitive deficits in AD. Aβ(1-42) interacts with and regulates the function of several nicotinic acetylcholine receptor (nAChR) subtypes. Aβ(1-42)has been shown to block long-term potentiation (LTP) in the hippocampus, which underlies learning and memory. Lynx1 is the endogenous neuromodulator of nAChRs in the brain. Recently, we demonstrated that water-soluble recombinant analogue of human Lynx1 (ws-Lynx1) competed with Aβ(1-42) for binding with nAChR subunits extracted from the brain, and abolished the Aβ(1-42)-induced cytotoxity on cortical neurons. Cortical Lynx1 level was decreased in transgenic 3xTg-AD mice. Here we studied the effect of Lynx1 on LTP blocked by Aβ(1-42). To define an effective concentration, 1 μM and 10 μM ws-Lynx1 was tested on L1 interneurons expressing α4β2 and α7 nAChR subtypes in the cortex using whole-cell patchclamp configuration and fast drug-application system. It was revealed that 1 μM ws-Lynx1 did not affect the ACh-evoked current, while 10 μM ws-Lynx1 increased the amplitude of ACh-evoked current up to ~ 18 %. Using selective inhibitors DhβE and MLA, we showed that observed potentiation is connected with α7-nAChRs. Pre-incubation of hippocampal slices with 10 μM ws-Lynx1 during one hour showed significant increase in LTP amplitude (~ 70 %) in CA1 region. Contrary, 200 nM Aβ(1-42) inhibited LTP. Co-application of Aβ(1-42) with ws-Lynx1 fully abolished the LTP blockade, caused by Aβ(1-42). Data obtained point on neuromodulator Lynx1 as important regulator of the cognitive processes, which could activate α7-nAChRs in the brain and prevent the blockade of long-term potentiation, caused by β-amyloid peptide. This might have functional and pathophysiological implications in relation to Alzheimer’s disease. Work was supported by the Russian Science Foundation (project # 16-14-00102)