Gunel Ayyubova

Microglia are central regulators of synaptic structure and cognitive function, yet under chronic inflammatory conditions, they can adopt stress-associated states associated with neuronal and synaptic vulnerability. Although inflammation-driven cognitive decline is often attributed to synapse loss, increasing evidence suggests that synaptic remodeling may precede or occur independently of overt synapse elimination. In this study, we combined behavioral testing, immunofluorescence, microglial morphometric analysis, and quantitative transmission electron microscopy to define structural correlates of inflammation-induced cognitive dysfunction and to evaluate the therapeutic potential of mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs). Chronic systemic inflammation was induced in mice by repeated lipopolysaccharide (LPS) administration, followed by intravenous MSC-EV treatment during the inflammatory phase. LPS exposure impaired working memory, object recognition, and spatial recognition memory without affecting locomotor activity. Immunofluorescence revealed increased CD68 immunoreactivity detected with the ED1 antibody clone within IBA1-positive cells, together with increased microglial soma area, reduced arborization area, and an elevated morphological index, consistent with microglial inflammatory remodeling and enhanced endolysosomal/phagolysosomal engagement. Ultrastructural analysis further demonstrated increased phagolysosomal inclusion burden, increased blood vessel-associated microglial profiles, elevated dark microglia-like profiles, reduced neuronal soma profile area, decreased SYN- and PSD95-positive structures, and coordinated pre- and postsynaptic alterations. Total excitatory synapse density showed only a non-significant numerical reduction, indicating synaptic vulnerability characterized primarily by structural remodeling rather than definitive synapse loss. MSC-EV treatment was associated with attenuated microglial inflammatory and morphometric alterations, reduced phagolysosomal and dark microglia-like ultrastructural features, partially restored synaptic marker-positive structures and synaptic ultrastructure, and improved hippocampus-dependent cognition, particularly spatial recognition memory. Together, these findings suggest that MSC-EVs are associated with partial normalization of inflammation-induced microglial, neuronal, and synaptic alterations.

Objective. This study aimed to evaluate the effects of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on histopathological, immunohistochemical, and ultrastructural changes in the hippocampus in a chronic lipopolysaccharide (LPS)-induced neuroinflammation model. Material and methods. Chronic neuroinflammation was induced in mice by daily intraperitoneal administration of LPS (750 μg/kg) for seven consecutive days. Following the final LPS injection, animals received an intravenous administration of 1 × 10⁶ hUC-MSCs via the tail vein. Histopathological changes in the hippocampus were evaluated using hematoxylin and eosin staining, microglial activation was assessed by Iba1 immunohistochemistry, and ultrastructural alterations were examined by transmission electron microscopy. Results. LPS administration resulted in neuronal degeneration, pyknotic changes, disruption of hippocampal architecture, and a significant increase in the number of Iba1-positive microglia. Transmission electron microscopy revealed activated microglia with numerous phagolysosomes and neuronal ultrastructural damage, including mitochondrial swelling. Administration of hUC-MSCs attenuated histopathological alterations, reduced microglial activation, and preserved neuronal ultrastructural integrity. Conclusion. These findings suggest that hUC-MSCs exhibit neuroprotective and immunomodulatory effects during chronic neuroinflammation, potentially representing a promising therapeutic strategy for neuroinflammatory disorders.

Emerging evidence suggests that viral infections may contribute to the onset and progression of Alzheimer’s disease (AD) and other forms of dementia. Understanding the mechanism of viral involvement in the pathogenesis of AD and related dementia (ADRD) could contribute to reducing the burden caused by these conditions, which affect a large portion of the aging population. Some studies indicate the link between AD and viral infections, notably coronaviruses and herpesviruses. In AD, excessive production of reactive oxygen species (ROS) results in the modifications of lipids, proteins, and nucleic acids, contributing to synaptic dysfunction and cognitive impairments. Experimental evidence suggests that viral infections linked to ADRD induce the cellular production of ROS, possibly contributing to the pathogenesis of these conditions. Despite significant advances in defining the roles of ROS in neurological disorders and viral infections, the specific roles of ROS in virus-associated ADRD have not been thoroughly investigated. The main objective of this review article is to comprehensively provide information on the experimental evidence for the production of ROS by viruses to help the readers investigate the role of ROS in the relationship between viral infections with ADRD.

The nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, discovered 20 years ago, is crucial in controlling innate immune reactions in Alzheimer's disease (AD). By initiating the release of inflammatory molecules (including caspases, IL-1β, and IL-18), the excessively activated inflammasome complex in microglia leads to chronic inflammation and neuronal death, resulting in the progression of cognitive deficiencies. Even though the involvement of NLRP3 has been implicated in neuroinflammation and widely explored in several studies, there are plenty of controversies regarding its precise roles and activation mechanisms in AD. Another prominent feature of AD is impairment in microglial autophagy, which can be either the cause or the consequence of NLRP3 activation and contributes to the aggregation of misfolded proteins and aberrant chronic inflammatory state seen in the disease course. Studies also demonstrate that intracellular buildup of dysfunctional and damaged mitochondria due to defective mitophagy enhances inflammasome activation, further suggesting that restoration of impaired autophagy and mitophagy can effectively suppress it, thereby reducing inflammation and protecting microglia and neurons. This review is primarily focused on the role of NLRP3 inflammasome in the etiopathology of AD, its interactions with microglial autophagy/mitophagy, and the latest developments in NLRP3 inflammasome-targeted therapeutic interventions being implicated for AD treatment.

Research indicates that brain-region-specific synapse loss and dysfunction are early hallmarks and stronger neurobiological correlates of cognitive decline in Alzheimer’s disease (AD) than amyloid plaque and neurofibrillary tangle counts or neuronal loss. Even though the precise mechanisms underlying increased synaptic pruning in AD are still unknown, it has been confirmed that dysregulation of the balance between complement activation and inhibition is a crucial driver of its pathology. The complement includes three distinct activation mechanisms, with the activation products C3a and C5a, potent inflammatory effectors, and a membrane attack complex (MAC) leading to cell lysis. Besides pro-inflammatory cytokines, the dysregulated complement proteins released by activated microglia bind to amyloid β at the synaptic regions and cause the microglia to engulf the synapses. Additionally, research indicating that microglia-removed synapses are not always degenerating and that suppression of synaptic engulfment can repair cognitive deficits points to an essential opportunity for intervention that can prevent the loss of intact synapses. In this study, we focus on the latest research on the role and mechanisms of complement-mediated microglial synaptic pruning at different stages of AD to find the right targets that could interfere with complement dysregulation and be relevant for therapeutic intervention at the early stages of the disease.

Neurological disorders have been reported in a large number of coronavirus disease 2019 (COVID-19) patients, suggesting that this disease may have long-term adverse neurological consequences. COVID-19 occurs from infection by a positive-sense single-stranded RNA virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The membrane fusion protein of SARS-CoV-2, the spike protein, binds to its human host receptor, angiotensin-converting enzyme 2 (ACE2), to initiate membrane fusion between the virus and host cell. The spike protein of SARS-CoV-2 contains the furin protease recognition site and its cleavage enhances the infectivity of this virus. The binding of SARS-CoV-2 to the ACE2 receptor has been shown to downregulate ACE2, thereby increasing the levels of pathogenic angiotensin II (Ang II). The furin protease cleaves between the S1 subunit of the spike protein with the binding domain toward ACE2 and the S2 subunit with the transmembrane domain that anchors to the viral membrane, and this activity releases the S1 subunit into the blood circulation. The released S1 subunit of the spike protein also binds to and downregulates ACE2, in turn increasing the level of Ang II. Considering that a viral particle contains many spike protein molecules, furin-dependent cleavage would release many free S1 protein molecules, each of which can downregulate ACE2, while infection with a viral particle only affects one ACE2 molecule. Therefore, the furin-dependent release of S1 protein would dramatically amplify the ability to downregulate ACE2 and produce Ang II. We hypothesize that this amplification mechanism that the virus possesses, but not the infection per se, is the major driving force behind COVID-19-associated neurological disorders.

Neurological disorders have been reported in a large number of coronavirus disease 2019 (COVID-19) patients, suggesting that this disease may have long-term adverse neurological consequences. COVID-19 occurs from the infection by a positive-sense single-stranded RNA virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The membrane fusion protein of SARS-CoV-2, the spike protein, binds to its human host receptor, angiotensin-converting enzyme 2 (ACE2), to initiate membrane fusion between the virus and host cell. The spike protein of SARS-CoV-2 contains the furin protease recognition site and its cleavage enhances the infectivity of this virus. The binding of SARS-CoV-2 to the ACE2 receptor has been shown to downregulate ACE2, thereby increasing the levels of pathogenic angiotensin II (Ang II). The furin protease cleaves between the S1 subunit of the spike protein with the binding domain toward ACE2 and the S2 subunit with the transmembrane domain that anchors to the viral membrane, and this activity releases the S1 subunit into the blood circulation. The released S1 subunit of the spike protein also binds to and downregulates ACE2, in turn, increasing the level of Ang II. Considering that a viral particle contains many spike protein molecules, furin-dependent cleavage would release many free S1 protein molecules each of which can downregulate ACE2, while the infection with a viral particle only affects one ACE2 molecule. Therefore, the furin-dependent release of S1 protein would dramatically amplify the ability to downregulate ACE2 and produce Ang II. We hypothesize that this amplification mechanism that the virus possesses, but not the infection per se, is the major driving force behind COVID-19 associated neurological disorders.

Extracellular vesicles (EVs) released by human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs) are enriched with miRNAs and proteins capable of mediating robust antiinflammatory activity. The lack of tumorigenic and immunogenic properties and ability to permeate the entire brain to incorporate into microglia following intranasal (IN) administrations makes them an attractive biologic for curtailing chronic neuroinflammation in neurodegenerative disorders. We tested the hypothesis that IN administrations of hiPSC-NSC-EVs can alleviate chronic neuroinflammation and cognitive impairments induced by the peripheral lipopolysaccharide (LPS) challenge. Adult male, C57BL/6J mice received intraperitoneal injections of LPS (0.75 mg/kg) for seven consecutive days. Then, the mice received either vehicle (VEH) or hiPSC-NSC-EVs (~ 10 × 10⁹ EVs/administration, thrice over 6 days). A month later, mice in all groups were investigated for cognitive function with behavioral tests and euthanized for histological and biochemical studies. Mice receiving VEH after LPS displayed deficits in associative recognition memory, temporal pattern processing, and pattern separation. Such impairments were associated with an increased incidence of activated microglia presenting NOD-, LRR-, and pyrin domain containing 3 (NLRP3) inflammasomes, elevated levels of NLRP3 inflammasome mediators and end products, and decreased neurogenesis in the hippocampus. In contrast, the various cognitive measures in mice receiving hiPSC-NSC-EVs after LPS were closer to naive mice. Significantly, these mice displayed diminished microglial activation, NLRP3 inflammasomes, proinflammatory cytokines, and a level of neurogenesis matching age-matched naïve controls. Thus, IN administrations of hiPSC-NSC-EVs are an efficacious approach to reducing chronic neuroinflammation-induced cognitive impairments.

Triggering receptor expressed on myeloid cells‐2 (TREM2) has crucial roles in microglial physiology, differentiation, metabolism and survival. Genome‐wide association studies (GWAS) show that genetic mutations of the TREM2 increase the risk of late‐onset Alzheimer's disease (AD) by two to four times, disrupting the microglial function in reducing the progression of the disease. Accumulating data show that TREM2 function in AD is related primarily to the clearance of soluble and insoluble amyloid beta (Aβ42) aggregates from the brain. TREM2 also ameliorates the pathological effects of activated microglia on neuronal tau pathology, demonstrating its protective anti‐inflammatory effects. However, since the excessive activation of TREM2 signalling can inhibit pro‐inflammatory reactions and suppress the role of microglia in immune surveillance, at the late stages of the disease, it might promote immune tolerance, which is detrimental. The contradictory effects of TREM2 mutations on brain amyloidopathy and tauopathy in multiple mouse models, as well as studies revealing various effects of TREM2 overexpression, complicate the understanding of the role that TREM2 plays in AD aetiopathogenesis. In this review, we summarize the latest developments regarding the significance of TREM2 signalling in the stability of microglial pro‐ and anti‐inflammatory activations and propose the mechanisms that should be targeted in the future to treat AD.