Dysregulation of expression of nicotinic acetylcholine receptors and Ly6/uPAR proteins in the cingulate gyrus of the cerebral cortex of patients with Alzheimer's disease

Alzheimer's disease (AD) is a common neurodegenerative disorder associated with the dysfunction of nicotinic acetylcholine receptors (nAChRs). The function of nAChRs is normally regulated by endogenous ligands, such as acetylcholine and three-finger proteins belonging to the Ly6/uPAR family. However, information on the involvement of these proteins in the pathogenesis of AD is lacking. In this study, by using a bioinformatic analysis, we identified increased mRNA levels of Ly6/uPAR proteins (Lynx1, Lynx2, SLURP-1, Ly6G6E, etc.) in the entorhinal, temporal, and frontal cortex in AD patients with neurodegenerative symptoms, as well as an increase in the mRNA level of Ly6E in the hippocampus in patients with asymptomatic AD. Furthermore, in the cortex and cerebellum, we identified multidirectional changes in the mRNA expression of different nAChR subunits and regulators of inflammation (CD59, CD177, Lypd2, Lypd4, and Lypd8) and metabolism (GPIHBP and Ly6D), also belonging to the Ly6/uPAR protein family. By using immunostaining and Western blotting, we confirmed increased protein levels of Lynx1, Lynx2, and the β2 nAChR subunit in the cingulate gyrus adjacent to the entorhinal cortex in patients with AD, as well as decreased protein levels of the α4 and α7 nAChR subunits. These findings point to complex dysregulation of the cholinergic system in the AD brain at the expression levels both of the individual nAChR subtypes and its natural modulators belonging to the Ly6/uPAR family.