Albert Acewicz

Transmembrane protein 106B (TMEM106B) is a lysosomal glycoprotein whose genetic polymorphisms contribute to the severity of neurodegenerative disorders associated with TDP‐43 pathology. Recent studies have revealed that TMEM106B can form amyloid filaments composed of C‐terminal fragments (CTFs) in the human brain. In the present study, we explored the relationships between TMEM106B, age, TDP‐43, and tau aggregates, and their roles in neurodegeneration. We used immunohistochemistry with an antibody against CTFs of TMEM106B on postmortem human brain fragments (amygdala, hippocampus, temporal cortex, frontal cortex, and basal ganglia) from patients with and without TDP‐43/tau pathology at different ages (6–94 years) and with different neurological conditions (subacute sclerosing panencephalitis, Alzheimer's disease, frontotemporal lobar degeneration, and neurologically healthy subjects). Our results revealed that TMEM106B CTF fibrillization is a common, nonspecific, diffuse, and age‐dependent phenomenon (appearing after >52 years of age) that affects neurons and neuroglia (most numerous in astrocytes and oligodendrocytes) and broad neuroanatomical regions (most severe in the temporal cortex). We did not find TMEM106B CTF aggregates in young subjects with TDP‐43/tau pathology (with subacute sclerosing panencephalitis), but we revealed differences in TMEM106B CTF fibrillization between Alzheimer's disease without TDP‐43 pathology, frontotemporal lobar degeneration with TDP‐43 pathology, and older healthy subjects without TDP‐43/tau pathology. Our results suggest that TMEM106B CTF aggregation is an age‐dependent phenomenon and may have a weak association with TDP‐43 or tau pathology, shedding new light on the complex relationships among TMEM106B, TDP‐43, and tau and the unclear role of TMEM106B fibril formation in the neurodegeneration process.

Progress in establishing environmental risk factors and, consequently, prophylactic measures for glial tumors, particularly for glioblastomas, is of utmost importance, considering the dismal prognosis and limited treatment options. This report surveyed updates on established and recently identified factors that can predispose a patient to glioma formation while highlighting possible mechanistic links and further research directions. In addition to established factors that increase the risk of glioma, i.e., brain irradiation and several genetic syndromes, another group consists of likely factors contributing to such risks, such as the use of tobacco and those yielding ambiguous results (e.g., UV exposure). Oxidative stress is a common denominator for several types of exposure, and a mechanistic background for other factors remains elusive. Nevertheless, the analysis of clinical and basic research strongly suggests that, apart from the effect of environmental stressors on DNA alterations and mutation burden, the impact of modifying the tumor microenvironment should be considered. Identifying the involvement of environmental hazards in gliomagenesis and glial tumor progression would lower overall risk by modifying clinical practice, patient management, and lifestyle choices. Further verifying the environmental hazards in glioma formation and progression would have far-reaching implications for neurologists, neurosurgeons, and patients.

Traumatic brain injury (TBI) is a significant contributor to mortality and is frequently linked to forensic and criminological inquiries. In the context of scientific and clinical progress, there is a continual need to explore new bioassays and data analysis methods for use in TBI diagnostics in both ante- and post-mortem individuals. Predominantly intra- and extra-synaptic proteins, such as synaptophysin (SYP) and neurogranin (NRGN) were to date potentially investigated as markers for TBI regarding their usefulness as a set of reliable biomarkers. This study aimed to elucidate and identify if elevated SYP and NRGN concentration levels in biofluids such as serum and CSF are seen in cases of TBI in a population-based autopsy screening. An additional comparative examination of the SYP and NRGN protein expression in the obtained brain tissue by performing immunohistochemical staining was done. The study was carried out using cases (n = 20) of severe head injury suspected as the cause of death and control cases (n = 20) of sudden death in the mechanism of cardiopulmonary failure. The biofluids, such as serum and cerebrospinal fluid (CSF) were collected within ∼24 h after death and compared using ELISA test. Brain specimens were similarly collected during forensic autopsies. In our study, we observed the elevated concentration levels of SYP and NRGN in serum and CSF. In anti-SYP staining of the frontal cortex, a significant, generalized reduction in the reaction was observed, within neurons and neuropil in the head injury group. In anti-NRGN staining of the frontal cortex, a significant, generalized homogenization of the reaction was observed both within the neuronal bodies and their axons. The possible implementation of synaptic biomarker assays offers an interesting and novel tool for investigation and research regarding TBI diagnosis and pathogenesis. This surrogate synatpic assay could be useful in clinical prognosis and risk calculation of non-fatal cases of TBI, regarding the development of neurodegenerative conditions of TBI individuals.

Alzheimer's disease is a progressive neurodegenerative disorder that disrupts the brain regions involved in memory and cognitive functions. This impairment ultimately results in severe deficits in memory, learning, reasoning, communication, and the ability to perform daily activities. Our research reveals a statistically significant decrease in the density of neural progenitor cells within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles in patients diagnosed with Alzheimer's disease. This reduction correlates with the disease's progression. As Alzheimer’s disease advances, cognitive functions decline progressively, leading to the identification of five distinct stages of β-amyloid distribution across various brain structures. Early symptoms include short-term memory deficits and learning difficulties, along with cognitive, psychiatric, and neurological disturbances. Given the hippocampus's essential role in these functions, one would expect to see substantial changes in this brain region. Thus, understanding adult neurogenesis is vital in Alzheimer’s disease, particularly since the hippocampus, a primary neurogenic area, is notably impacted in affected individuals.

Subacute sclerosing panencephalitis (SSPE) is a fatal, slowly progressive brain disorder caused by a mutated measles virus. Both subacute inflammatory and neurodegenerative mechanisms appear to play significant roles in the pathogenesis. TAR DNA-binding protein 43 (TDP-43) inclusions are a common co-pathology in several neurodegenerative disorders with diverse pathogenesis. In the present study, we examined brains of 16 autopsied SSPE patients for the presence of TDP-43 pathology and possible associations with tau pathology. Immunohistochemical staining identified TDP-43 inclusions in 31% of SSPE cases. TDP-43 pathology was widely distributed in the brains, most severely in the atrophied cerebral cortex (temporal and parietal), and most frequently as tangle- and thread-like neuronal cytoplasmic inclusions. It was associated with longer disease duration (>4 years) and tau pathology (all TDP-43-positive cases had tau-positive neurofibrillary tangles). This study demonstrates for the first time an association between TDP-43 pathology and SSPE. The co-occurrence of TDP-43 and tau aggregates and correlation with the disease duration suggest that both pathological proteins are involved in the neurodegenerative process induced by viral inflammation.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with the onset of neurological and psychiatric symptoms during and after the acute phase of illness. Inflammation and hypoxia induced by SARS-CoV-2 affect brain regions essential for fine motor function, learning, memory, and emotional responses. The mechanisms of these central nervous system symptoms remain largely unknown. While looking for the causes of neurological deficits, we conducted a study on how SARS-CoV-2 affects neurogenesis. In this study, we compared a control group with a group of patients diagnosed with COVID-19. Analysis of the expression of neurogenesis markers showed a decrease in the density of neuronal progenitor cells and newborn neurons in the SARS-CoV-2 group. Analysis of COVID-19 patients revealed increased microglial activation compared with the control group. The unfavorable effect of the inflammatory process in the brain associated with COVID-19 disease increases the concentration of cytokines that negatively affect adult human neurogenesis.