Аннотация: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).