Yu. K. Komleva’s research while affiliated with McKnight Brain Institute and other places

Aging is accompanied by a significant increase in the number of age-associated diseases, which has a serious impact on the individual and society. Against the background of a steady increase in the number of elderly people, the concept of frailty is now actively used in medicine. It implies increased vulnerability to various health problems associated with a decrease in physiological reserves against the background of aging, including accelerated aging in neurodegeneration. Psychosocial, environmental and age-related biological factors contribute to the decline in physical and cognitive abilities. Their culmination leads to the condition known as physical frailty, in addition to which a lot of researchers are emphasizing the phenomenon of cognitive frailty as a manifestation of cognitive impairment on the background of increasing physical weakness. The review presents an up-to-date analysis of the literature on frailty as a multidimensional and dynamic process, focusing on the role of cognitive reserve in aging. Evidence from cross-sectional and longitudinal studies is reviewed, showing that cognitive frailty is associated with increased risk of disability, impaired quality of life, hospitalizations, mortality, and neurocognitive disorders. This emphasizes the importance of introducing this concept into the clinical practice of geriatricians and neurologists. The article reviews data on the epidemiology, diagnostic approaches used, and perspectives.

The article examines the relationship between social fragility and cognitive impairment (CI) in elderly in the context of population ageing and the increasing proportion of age-related diseases. Social fragility is defined as a progressive loss of social resources, including support and social engagement, which is associated with an increased risk of depression, cognitive decline and dementia. A comprehensive review of studies published between 2017, and November 2024 was conducted to examine social fragility and its association with CI. The paper provides an overview of current approaches to assessing social fragility, including the use of indices and scales. The main risk factors, including depression, physical activity and CI, and the mechanisms underlying this relationship are analyzed in detail. Particular attention is paid to the consequences of social fragility for cognitive health and possible prevention strategies. The article discusses the role of social isolation, loneliness, reduced physical activity and diminished social interactions as key aspects that increase the risk of cognitive decline. It also points out that maintaining an active social network and participating in social life can slow the progression of CI and improve the quality of life of elderly. Our work emphasizes the need for an interdisciplinary approach to the diagnosis and treatment of social fragility, which includes the development of social relationships, the promotion of physical activity and the participation in group activities. These measures can help to strengthen cognitive reserves, reduce the negative effects of social fragility and ensure an active, long life for the elderly population.

The NLRP3 inflammasome is known to play a significant role in the development of neurodegeneration and physiological aging, as well as the development of metabolic inflammation, which has generated significant interest in the scientific community in finding effective inhibitors of the NLRP3 inflammasome and assessing their effects. The purpose of this study was to evaluate the effect of pharmacological modulation of NLRP3 activity using an indirect NLRP3 inflammasome inhibitor, glibenclamide, on the expression of metaflammasome components in in vitro brain cells obtained from middle-aged mice. The study revealed that glibenclamide reduces the expression of pro-inflammatory markers NLRP3 and IL18 in cell culture, which in turn leads to the prevention of phosphorylation of protein kinases of the metaflammasome complex – PKR and IKKβ. However, we did not observe changes in the expression of pathologically phosphorylated IRS, as well as in the number of senescent cells in cultures after the exposure to glibenclamide.

Decreased energy metabolism in the brain correlates with cognitive impairment in Alzheimer’s disease. Accumulating experimental data indicate that lactate transporters and monocarboxylate transporters (MCTs) are directly involved in cerebral energy metabolism. However, to date, changes in lactate levels and MCT content in Alzheimer’s disease remain unclear. The aim of the study was to study the content of lactate and of its transporters – MCT1 and MCT2 in cells of neuronal, astroglial and endothelial nature under acute toxic effects of beta-amyloid (Aβ1–42) in vitro and in vivo. Under conditions of acute toxic action of Aβ1–42 in vivo, a significant (P ≤ 0.05) decrease in the level of lactate in the hippocampal tissue and an increase (P ≤ 0.05) in the dialysate were found. At the same time, a low (P ≤ 0.05) levels of MCT1 and MCT2 was set. In vitro, significantly high (P ≤ 0.05) production of lactate by astrocytes was revealed, coupled with low (P ≤ 0.05) level of MCT2 on neurons. Thus, it was found that Aβ1–42 causes a decrease in the level of lactate in the hippocampal tissue and an increase in its level in dialysate in vivo, which correlates with the impaired level of MCT1 and MCT2. This indicates a violation of energy metabolism due to the acute toxic effect of Aβ1–42. At the same time, the revealed increase in the production of lactate by astrocytes in vitro may indicate the inclusion of a compensatory mechanism aimed at maintaining the astrocyte-neuronal interaction.

Aim. To study the insulin (INS) gene expression, insulin and lactate levels, expression of Fe65 adapter protein, and level of oxidative DNA damage marker γH2AX in different brain areas in the experimental model of Alzheimer's disease. Materials and Methods. Male, 4-month-old C57BL/6 mice received either intrahippocampal injection of β-amyloid (C57BL/6 + Aβ 1-42) or phosphate-buffered saline (C57BL/6 + PBS). Insulin (INS) gene expression in the hippocampus and amygdala was assessed by means of reverse transcription-polymerase chain reaction. Levels of lactate and insulin in different brain areas were measured by enzyme-linked immunosorbent assay. Expression of Fe65 adapter protein and γH2AX in the hippocampus was studied by immunofluorescence staining followed by confocal microscopy. Results. We found an overexpression of the INS gene in the hippocampus and amygdala, an increase in lactate level in the hippocampus, and slightly increased insulin level in the amygdala of mice with Alzheimer's disease as compared with the control group. Neurodegeneration was accompanied by an elevated endothelial expression of Fe65 adapter protein (p= 0.04) and γH2AX in hippocampal neurons (p = 0.04). Conclusion. Alzheimer's disease neurodegeneration is accompanied by a disrupted insulin signaling and impaired glucose metabolism in the hippocampus and amygdala. This further leads to a neuronal accumulation of γH2AX and impaired amyloid precursor protein proteolysis because of insulin inability to inhibit its interaction with the Fe65 adapter protein and to prevent formation and deposition of β-amyloid.