Alzheimer's disease (AD) is a neurodegenerative disease characterized by multiple cognitive impairments, amyloid peptide accumulation, neuroinflammation, synaptic dysfunction, and degradation of astrocytes and neurons. There are no effective drugs for AD today. Potential targets for drugs that improve cognitive function are nicotinic acetylcholine receptors (nAChRs), whose dysfunction is associated with neurodegeneration. The creation of specific modulators of individual nAChR subtypes may be a promising approach for the development of new drugs against AD. Lynx1 is a human membrane-anchored Ly6/uPAR protein that colocalizes with nAChR a7 and a4b2 types in the brain and modulates their function. Lynx1 is involved in memory and learning processes and is a regulator of neuronal and synaptic plasticity; knockout of the lynx1 gene leads to the destruction of the myelin sheath during aging. The authors of the project showed that Lynx1 potentiates a7-nAChR, competes with Ab1-42 (the most toxic form of amyloid peptide) for binding to a7-nAChR, compensates for the deterioration of synaptic plasticity caused by Ab1-42, and Lynx1 expression is reduced in the brain of mice modeling AD. Also, the authors of the project showed that intranasal therapy with recombinant water-soluble Lynx1 leads to accumulation of the drug in the brain of mice and improvement of cognitive processes. The human Lypd6 protein, also a membrane-anchored Ly6/uPAR protein, inhibits a7- and a3b4-nAChRs, regulates neuronal plasticity, but is a negative regulator of nAChRs and synaptic plasticity. Lypd6b is a neuromodulator of nAChRs in the brain homologous to Lypd6; the authors of the project determined its spatial structure and showed that its expression, as well as expression of Lypd6, is reduced in the hippocampus of mice modeling AD, but its pharmacology has been poorly studied. Human Ly6/uPAR protein PSCA is expressed in the human cerebral cortex and interacts with a4-nAChR. PSCA expression is increased in the cortex of mouse models of AD and in the brain of AD patients by 70%. The mechanism of action of PSCA is currently unknown. The goal of the project is to study the relationship between changes in the expression of Lynx1, Lypd6, Lypd6b and PSCA proteins in the mammalian brain with the development of cognitive impairment observed in neurodegeneration and AD. The molecular mechanisms underlying changes in the expression of these proteins, as well as the consequences of the cognitive function changes, including those related to the regulation of the brain's cholinergic system, synaptic and neuronal plasticity, and the morphology of neurons and astrocytes, will be studied. The possibility of compensating these changes using recombinant analogues of Lynx1, Lypd6, Lypd6b and PSCA and their mimetics will also be studied. The work will use primary cell lines of neurons and astrocytes, as well as animal models (rodent, including transgenic variants). The project will conduct a comparative analysis of the expression of Lynx1, Lypd6, Lypd6b and PSCA in primary neurons and astrocytes, as well as in various brain structures of mice. The effects of Lynx1, Lypd6, Lypd6b and PSCA on cognitive processes and on intracellular signaling cascades will be investigated using primary cultures of neurons and astrocytes and surviving cortical and hippocampal slices from mice. Neuromodulators with pro-cognitive properties will be used for systemic therapy in mice models of AD. For the first time, the pharmacology of Lypd6b and PSCA will be studied and the spatial structure of PSCA will be determined. This will make it possible to build models of neuromodulator complexes with nAChRs in a membrane environment, compare them with each other, and develop on their basis mimetics to improve cognitive function, the applicability of which for the control of neurodegenerative processes will be studied in an animal model of AD. The results of the study may be useful in creating new biomedical drugs with targeted action that can significantly improve the quality of life of people suffering from cognitive dysfunction during aging and a number of neurodegenerative diseases.