Background: the general lifespan has been prolonged greatly during the past century, and the incidence of age-associated diseases, including neurodegenerative ones, has increased as well. However, modelling of age-related pathologies is mostly conducted on adult rodents. We studied morphofunctional changes in the brain and peripheral blood of adult Wistar rats in comparison with old Wistar rats to determine age-related physiological changes and differences in adaptive reactions to AlCl₃ exposure. Methods: the work was performed on adult and old male Wistar rats. The animals consumed a 100 mg/kg solution of AlCl₃ each day for 60 days. Morphological changes of neurons and microglia, mRNA expression levels of pro-inflammatory and anti-inflammatory cytokines, microglia activation markers, amyloid-related proteins, and hallmarks of cellular senescence, monocyte, and lymphocyte subpopulations in the peripheral blood were examined. Results: old rats showed increasing hyperchromic neurons in the hippocampus; activation of microglia; upregulation of pro-inflammatory cytokines and cellular senescence markers; downregulation of anti-inflammatory cytokines; and Hif-1a and a decrease in B-cells and monocyte in peripheral blood. Conclusion: compared to young animals, aged rats respond to aluminum exposure with a severe decline of most cells’ function and irreversible neuronal loss. Regarding all reported data, neurodegeneration modelling and investigating of factors capable of accelerating or preventing it should be performed in experimental work on aged animals.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases leading to dementia. There is no effective treatments for this disease so far, as well as a consensus concerning the mechanisms of its pathogenesis initiation. Obtaining data on them in vivo is possible only by modeling neurodegeneration in laboratory animals. Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases leading to dementia. There is no effective treatments for this disease so far, as well as a consensus concerning the mechanisms of its pathogenesis initiation. Obtaining data on them in vivo is possible only by modeling neurodegeneration in laboratory animals. Among the various theories of the initiation of neurodegeneration, the impact of microglia is vigorously studied recently, as well as inflammaging, which is a term for chronic age-related low-grade systemic inflammation. It manifests in the increasing number of senescent cells with senescence-associated secretory phenotype (SASP). Eventually, it leads to manifestation and progression of age-related diseases, such as AD. The aim of the study was to evaluate age-related changes in microglia, pro- and anti-inflammatory cytokines expression levels in the brain, as well as ones of microglial activation, and also subpopulations of lymphocytes in peripheral blood. We used male Wistar rats of two age groups, which were composed of old (age 24 months) and adult (age 3 months) rodents, without any additional exposure. In the hippocampus, morphological changes in microglia were assessed on preparations stained with antibodies to Iba1. In the prefrontal cortex, RT-qPCR was used to study the level of expression of pro-inflammatory IL-6 and TNFa, anti-inflammatory IL-10 and TGF-b cytokines, as well as microglial activation markers iNOS and MMP-9. In the peripheral blood, the relative numbers of the main subpopulations of lymphocytes and monocyte were measured by flow cytometry. It was shown that, compared with adult rats, old animals are characterized by significant changes in the morphology of microglia, an increase in the level of expression of pro-inflammatory and a decrease in anti-inflammatory cytokines, and an increase in microglia activation markers. With aging, a decrease in the percentage of monocytes and B cells in peripheral blood was observed. These data indicate the development of inflammaging, which displays itself in microglia activation, a shift in the balance of cytokine production towards pro-inflammatory ones, and, as a result, activation of the migration of monocytes and B lymphocytes from the blood into tissues. Thus, it is justified to study the role of inflammation in the development of AD in old animals whose physiological state corresponds to that in humans. Further research in this area will expand the understanding of the mechanisms of initiation and progression of neurodegeneration, which is necessary for the development of novel and effective therapeutic approaches to the treatment of AD.

Maternal immune activation (MIA) during pregnancy is a recognized risk factor for neurodevelopmental and neurodegenerative disorders, including Alzheimer’s disease. Although the long-term consequences of prenatal inflammation have been extensively investigated, the influence of biological sex on age-related behavioral and hippocampal alterations remains insufficiently understood. MIA was induced in pregnant Wistar rats by the intraperitoneal administration of lipopolysaccharide (100 μg/kg) on gestational day 17. Male and female offspring were examined at 12 months of age. Behavioral patterns were assessed using the Morris water maze and elevated plus maze. Hippocampal neuronal morphology and microglial and astrocytic phenotypes were evaluated by histology and IHC, while the expression of genes associated with inflammation, neurodegeneration, neuroplasticity, oxidative stress, and neurogenesis was determined by RT-qPCR. Prenatal LPS exposure produced persistent behavioral alterations in both sexes but with distinct phenotypes. Both male and female offspring exhibited increased anxiety-like behavior, whereas females showed reduced exploratory activity during spatial memory testing. Female offspring demonstrated more pronounced hippocampal pathology, including an increased relative number of pyknotic hyperchromic neurons, a reduced ramified-to-amoeboid microglia ratio, decreased Bdnf, and selective upregulation of Bace1 and Usp11, potentially indicating enhanced susceptibility to neurodegenerative processes. In contrast, males maintained predominantly ramified microglia morphology and showed increased expression of the neuronal progenitor gene Pax6, possibly suggesting the activation of compensatory mechanisms. Both sexes exhibited hippocampal upregulation of Il18, Arg1, Mmp9, Ntrk2, and Gpx4, consistent with chronic pro-inflammatory background accompanied by adaptive antioxidant and anti-inflammatory responses. Prenatal immune activation induces long-lasting behavioral, morphological, and molecular alterations that persist into middle age and exhibit marked sexual dimorphism. Female offspring appear more vulnerable to pro-neurodegenerative changes, whereas male offspring activate compensatory neuroprotective pathways that might partially preserve hippocampal function despite sustained pro-inflammatory reactions. These findings highlight sex as a critical biological variable in the long-term consequences of prenatal inflammation and may facilitate the identification of early biomarkers and therapeutic targets for MIA-associated neuropsychiatric and neurodegenerative disorders.

Bisphenol A (BPA) is a widespread plasticizer widely used in the food industry worldwide. However, a consensus on the safe level of its daily intake does not currently exist, while there are numerous data pointing to a link between prenatal exposure to BPA and early neuropsychiatric disorders, such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). The global average human-equivalent dose of BPA is estimated at 30 ng/kg body weight/day. Thus, the research herein was conducted on newborn and juvenile rat offspring of both sexes delivered from rats treated with 30 ng/kg body weight/day orally from day 6 to 21 of pregnancy and for a further 21 days during lactation. Our data indicate that prenatal exposure to 30 ng/kg/day from gestation day 6 to delivery induced sexually dimorphic, region-specific alterations in the neonatal (PD1) rat brains, impacting inflammatory reactions, estrogen receptor signaling, and neural progenitor dynamics. Prenatally BPA-treated males exhibited a pro-inflammatory state characterized by an increased total number of ramified Iba1+ microglia cells in the hippocampus alongside upregulation of Aif1, Nfkb, Tnf, Il1b, and Hif1a. Conversely, prenatally BPA-treated females showed only an increased total number of hippocampal Iba1+ cells and displayed inflammatory resilience, lacking upregulation of these markers. Both sexes exhibited a pro-inflammatory state in the prefrontal cortex via upregulation of Nfkb, Tnf, Il1b, and Hif1a. While both sexes showed decreased Tgfb in the prefrontal cortex, they deployed distinct compensatory responses: males upregulated the neuroprotector Igf1 only in the hippocampus, whereas in females, it was upregulated in both the hippocampus and the prefrontal cortex. Estrogen receptor expression was also highly dimorphic. In the hippocampus, males displayed an imbalance via Esr1 upregulation and Esr2 downregulation, while females showed Esr2 downregulation alone. In the prefrontal cortex, these transcriptional profiles were the opposite. Finally, neural progenitor markers were altered. In the prefrontal cortex, BPA drove the upregulation of Sox2 and Pax6 in males but Sox9 in females; in the hippocampus, only Pax6 was upregulated, and only in males. The PAX6 protein level in the hippocampus was significantly increased in males but decreased in females. In juvenile offspring (PD21), behavioral patterns characterized by hyper-exploration, increased environmental investigation, and heightened emotional reactivity during social exposure were more pronounced in female offspring. These baseline neonatal disparities followed by behavioral changes underscore the necessity of sex-specific approaches when evaluating early-life neurodevelopment and subsequent adult behavioral and biological vulnerabilities.