A number of recent studies have demonstrated the importance of investigating mitochondrial dynamics mechanisms in Alzheimer’s disease (AD). This study involved an immunohistochemical analysis of mitochondrial dynamics markers Opa-1, Mfn-2, and Drp-1 in neurons of the middle frontal gyrus, anterior cingulate gyrus, head of the caudate nucleus, hippocampus, and inferior parietal lobule using autopsy material from AD patients. The comparison was made with similar brain regions in autopsy material from elderly and young patients. Additionally, changes in these markers in AD were correlated with the distribution of pathological amyloid aggregates in the corresponding regions. Our findings suggest specific features of metabolic process alterations in neurons in AD, which are not limited to a single brain region but involve multiple areas and exhibit a uniform pattern. Our data are significant for understanding the pathogenesis of this disease and aging in general, and may serve as a basis for developing targeted therapy for AD.

Expanding research indicates that oxidative stress, particularly mitochondrial oxidative stress, is one of the key components in the pathogenesis of Alzheimer’s disease (AD). Mitochondrial oxidative stress is largely driven by impaired function of electron transport chain (ETC) complexes and their regulators. This study conducted an immunohistochemical analysis of ETC proteins (α-subunit of complex V, subunits MTCO1 and MTCO2 of complex IV) and mitochondrial complex V inhibitor IF-1 in the neurons of the caudate nucleus head, hippocampus, anterior cingulate gyrus, middle frontal gyrus, and inferior parietal lobule using autopsy material from patients with sporadic AD. Comparisons were made with similar brain regions in autopsy material from age-matched elderly patients and young patients. The results revealed a pattern of ETC impairment in AD fundamentally distinct from that observed in physiological aging. Specifically, a hippocampus-specific failure of the adaptive response was identified: unlike other brain regions, compensatory upregulation of ATP synthase does not occur here despite critical reduction in the protective protein IF-1, directly explaining the heightened vulnerability of hippocampal neurons to damage. Our data deepen the understanding of AD pathogenesis by highlighting region-specific mitochondrial defects as promising targets for tailored therapeutic intervention.

Arterial hypertension is a socially significant disease, one of whose complications is cerebral ischemia. Various mechanisms are involved in the adaptation of neurons to hypoxia, including those modulating mitochondrial activity, the autophagy system, and the regulation of apoptosis. Objective. To study the immunohistochemical features of markers of autophagy, mitochondrial dynamics and regulation of apoptosis in neurons during chronic diffuse and focal ischemia in grade II-III hypertension in the region of the basal ganglia (BG) of humans. Material and methods. The brain of deceased patients with grade II—III hypertension with and without lacunar infarcts (LI) in the area of the BG, and control cases with the absence of hypertension, was studied. Immunohistochemical analysis of the proteins Drp-1, Opa-1, Mfn-2, Beclin-1, SQSTM-1, and Bcl-2 was performed, followed by determination of their staining intensity in three zones at different distances from the LI center. Results. The LI zones were characterized by varying changes in the studied markers. Peri-infarction zones 1 and 2, closest to the LI center, were characterized by increased levels of the markers Bcl-2, Beclin-1, SQSTM1, Opa-1, and Mfn-2 compared to control cases. In the zone furthest from the infarction center, a decrease in the SQSTM-1 marker and an increase in the Drp-1 marker were observed compared to other LI zones. In cases of hypertension without the development of LI, an increase in the Beclin-1 level and an increase in the Opa-1 level were observed compared to control cases. Conclusion. The degree of ischemic damage can determine the pattern of the neuron’s adaptive response: in areas with the most severe ischemic damage, the Bcl-2-mediated mechanism of protection from apoptosis is activated and the balance of mitochondrial dynamics shifts towards the predominance of the fusion of these organelles. With a relatively low severity of ischemia, a shift in the balance of mitochondrial dynamics towards the division of these organelles was found; in the case of moderate severity of ischemic damage, activation of both division and fusion of mitochondria is observed.

INTRODUCTION. Osteoporosis is a leading cause of morbidity, disability, reduced quality of life, and premature mortality in the elderly population. Denosumab is a treatment for osteoporosis; however, denosumab discontinuation may cause a rebound effect, which is a severe adverse drug reaction (ADR) leading to an increase in the rate of bone tissue loss. Studying the mechanism of the rebound effect and potential ways to manage it can improve the safety of denosumab therapy.AIM. This study aimed to summarise up-to-date information regarding the mechanism of the rebound effect and ways to manage it after denosumab discontinuation.DISCUSSION. Osteoporosis results from an imbalance in bone remodelling. Recent studies have shown that mature osteoclasts are able to fission into osteomorphs, which separate from the polykaryon and fuse with neighbouring osteoclasts or other osteomorphs (osteoclast recycling). The mechanism of action of denosumab is based on the inhibition of osteoclast recycling, which results in the accumulation of pre-osteoclasts and osteomorphs. Research into processes occurring in bone tissue shows that denosumab creates a pool of induced cells, and when denosumab therapy is discontinued, these induced cells quite quickly and abundantly differentiate into osteoclasts causing bone resorption (rebound effect) and increasing the risk of fractures. In order to improve mineral bone density and to prevent fractures after denosumab discontinuation, it is reasonable to use antiresorptive medicines from the bisphosphonate class. Bisphosphonates accumulate in bone tissue and concentrate in areas of active bone metabolism.CONCLUSIONS. Further studies of the rebound effect mechanism, including a deeper understanding of the role of osteomorphs in osteogenesis, will improve the measures taken to reduce the risk of fractures after denosumab discontinuation. Further research is needed to evaluate the effect of antiresorptives on bone tissue loss after denosumab discontinuation.

Introduction. Alzheimer’s disease is the most common cause of dementia; however, its pathogenesis remains poorly understood. Autophagy dysfunction, a key process for the clearance of damaged proteins and organelles, plays a significant role in neurodegeneration. However, data on the region-specific distribution of autophagy markers in motor areas of the brain in Alzheimer’s disease are extremely limited. Therefore, this study aimed to immunohistochemically evaluate autophagy markers in neurons of the head of the caudate nucleus and motor cortex of patients with Alzheimer’s disease. Materials and methods. An immunohistochemical study was performed on brain autopsies from three groups: patients with Alzheimer’s disease (n=15), healthy aging participants (n=20), and young patients (n=20). The intensity of the immunohistochemical reaction was assessed in the perikarya of neurons in the head of the caudate nucleus (striatum) and in neurons in layers 3 and 5 of the motor cortex. Results. With aging, neurons in the head of the caudate nucleus exhibit decreased levels of the autophagosome-associated proteins Beclin-1 and LC3b, accompanied by increased levels of the damaged mitochondria marker pS65-Ub and the lysosomal protein LAMP2. In Alzheimer’s disease, neuronal pS65-Ub levels are further elevated, whereas the expression of Beclin-1, LC3b, and LAMP2 significantly reduces. In layers 3 and 5 of the motor cortex, aging is associated with increased levels of Ub and pS65-Ub, together with decreased Beclin-1 and LC3b, while LAMP2 levels remain comparable to those in the young group. In Alzheimer’s disease, Ub, Beclin-1, and LC3b levels remain unchanged relative to the aging group, whereas p-Ub and LAMP2 levels are decreased. Conclusion. In Alzheimer’s disease, a region-specific pattern of autophagolysosomal dysfunction develops in the motor regions of the brain: in the striatum, the damage is more pronounced, whereas in the motor cortex, a less pronounced isolated lysosomal deficit predominates with preserved autophagy initiation. Keywords: autophagy, neurodegeneration, Alzheimer’s disease, motor cortex, striatum

Hypoxia-inducible factors (HIF-1α, HIF-2α, HIF-3α) regulate cellular adaptation to oxygen deprivation, but their region-specific roles in Alzheimer’s disease (AD) and AD with cerebral amyloid angiopathy (CAA) remain unclear. Using post-mortem human brain tissue from aging, AD, and AD + CAA groups, we measured all three HIF isoforms in hippocampal subfields (CA1, CA2, CA4, dentate gyrus) and anterior cingulate cortex (ACC) layers 3 and 5. In the AD hippocampus, two distinct patterns emerged: ischemia-resistant regions (CA4, DG) maintained HIF-2α and showed relative resilience, whereas vulnerable regions (CA1, CA2) exhibited HIF-1α upregulation, HIF-3α loss, and HIF-2α dysregulation. The ACC contrasts sharply with the hippocampus by preserving coordinated HIF-1α/HIF-3α regulation during aging and AD, with layer-specific divergence (exhaustion in layer 3 vs. resilience in layer 5) emerging only upon addition of CAA. Notably, HIF-2α in ACC neurons remains stably elevated across all conditions. Taken together, our results highlight HIF-2α as a potential contributor to regional vulnerability and raise the possibility that maintaining HIF-2α levels, in addition to or instead of modulating HIF-1α, could be worthy of further investigation in the context of AD and related vascular changes.