Frailty is a complex geriatric syndrome associated with biological vulnerability to stressors and decreased physiological reserve. Its etiology and pathogenesis are not completely understood, although various causes and complex pathways have been proposed. Immune system alterations (immunosenescence and "InflammAging") have been suggested to contribute to frailty, but a precise causative role of such alterations remains to be determined. Genetic studies support the suggestion of immune system involvement in frailty: genetic variants in genes involved in immune system function have been associated with the syndrome. Interestingly, nutritional status, through its effects on cellular metabolism, may also influence the immune system, i.e. hormone and cytokine (mainly adipocytokine) levels, and immune cell populations and function, increasing inflammation and contributing to frailty. This review aims to discuss the role of immune system alterations in frailty, analyzing the role of genetic factors in frailty onset and the impact of diet on inflammation and, in turn, on frailty.

BACKGROUND/OBJECTIVES: Increasing evidence suggests the importance of neuroinflammation in the pathogenesis of Alzheimer’s disease (AD), which is a complex neurodegenerative disorder. Complement activation occurs in the brain of patients with AD and seems to contribute to an important local inflammatory state. Increased expression of the fourth serum complement component 4 (C4) has been observed in AD patients in many studies. This protein has two isoforms, encoded by two genes: C4A and C4B localized to the HLA class III region. These genes exhibit copy number variations (CNVs) and this different gene copy number can influence C4 protein levels. We focalized our attention on these two genes, determining the distribution of CNVs in AD patients, compared with healthy controls, in order to analyse their possible involvement in AD pathogenesis. METHODS: We investigated 191 AD patients and 300 healthy controls. The C4A and C4B copy numbers were assessed by quantitative PCR (qPCR). RESULTS: The results obtained showed a statistically significant increase in the number of copies for both C4A and C4B in AD patients, compared with healthy controls (p<0,001). CONCLUSION: The presence of high C4A and C4B copy numbers in AD patients could explain the increased C4 protein expression observed in AD patients, thus highlighting a possible role for C4A and C4B CNVs in the risk of developing AD.

Human pluripotent stem cell (hPSC)-derived neuron cultures have emerged as models of electrical activity in the human brain. Microelectrode arrays (MEAs) measure changes in the extracellular electric potential of cell cultures or tissues and enable the recording of neuronal network activity. MEAs have been applied to both human subjects and hPSC-derived brain models. Here, we review the literature on the functional characterization of hPSC-derived two- and three-dimensional brain models with MEAs and examine their network function in physiological and pathological contexts. We also summarize MEA results from the human brain and compare them to the literature on MEA recordings of hPSC-derived brain models. MEA recordings have shown network activity in two-dimensional hPSC-derived brain models that is comparable to the human brain and revealed pathology-associated changes in disease models. Three-dimensional hPSC-derived models such as brain organoids possess a more relevant microenvironment, tissue architecture and potential for modeling the network activity with more complexity than two-dimensional models. hPSC-derived brain models recapitulate many aspects of network function in the human brain and provide valid disease models, but certain advancements in differentiation methods, bioengineering and available MEA technology are needed for these approaches to reach their full potential.

Stroke is one of the leading causes of death worldwide and currently only few therapeutic options are available. Stroke is a sexually dimorphic disease contributing to the difficulty in finding efficient treatments. Poststroke neuroinflammation is geared largely by brain microglia and infiltrating peripheral immune cells and largely contributes to sex differences in the outcome of stroke. Microglia, since very early in the development, are sexually divergent, imprinting specific sex-related features. The diversity in terms of microglial density, morphology, and transcriptomic and proteomic profiles between sexes remains in the adulthood and is likely to contribute to the observed sex-differences on the postischemic inflammation. The impact of sexual hormones is fundamental: changes in terms of risk and severity have been observed for females before and after menopause underlining the importance of altered circulating sexual hormones. Moreover, aging is a driving force for changes that interact with sex, shifting the inflammatory response in a sex-dependent manner. This review summarizes the present literature on sex differences in stroke-induced inflammatory responses, with the focus on different microglial responses along lifespan.

The complex scenario of multiple sclerosis (MS) pathology involves several mechanisms, including oxidative stress response. The heat shock proteins (HSPs) are important for the protection of the cells; however, their role in MS is not clear. The present research is focused on the response of peripheral blood mononuclear cells (PBMCs) to oxidative stress and to the involvement of HSP70-2 (a protein coded by the HSPA1B gene, located in the MHC class III). To this aim, we challenged PBMCs from MS patients and healthy controls with hydrogen peroxide. Specifically, PBMCs mitochondrial activity, HSP70-2 protein expression and the production of intracellular reactive oxygen species were assessed. These parameters were also related to the HSP70-2 rs1061581 polymorphism, which is linked to the risk of developing MS. Moreover, mitochondrial activity and HSP70-2 protein levels were also related to disease severity. Overall, our results indicate that PBMCs, from both MS patients and healthy controls, may display a similar response towards an oxidative insult; within this context, HSP70-2 does not seem to be central in the protection of PBMCs. Nevertheless, the HSP70-2 rs1061581 polymorphism is related to ROS levels and appears to have a role in the different expression of HSP70-2 under oxidative stimulus.