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Pathophysiology of chronic neurodegeneration is mainly based on complex mechanisms related to aberrant signal transduction, excitation/inhibition imbalance, excitotoxicity, synaptic dysfunction, oxidative stress, proteotoxicity and protein misfolding, local insulin resistance and metabolic dysfunction, excessive cell death, development of glia-supported neuroinflammation, and failure of neurogenesis. These mechanisms tightly associate with dramatic alterations in the structure and activity of the neurovascular unit (NVU) and the blood–brain barrier (BBB). NVU is an ensemble of brain cells (brain microvessel endothelial cells (BMECs), astrocytes, pericytes, neurons, and microglia) serving for the adjustment of cell-to-cell interactions, metabolic coupling, local microcirculation, and neuronal excitability to the actual needs of the brain. The part of the NVU known as a BBB controls selective access of endogenous and exogenous molecules to the brain tissue and efflux of metabolites to the blood, thereby providing maintenance of brain chemical homeostasis critical for efficient signal transduction and brain plasticity. In Alzheimer’s disease, mitochondria are the target organelles for amyloid-induced neurodegeneration and alterations in NVU metabolic coupling or BBB breakdown. In this review we discuss understandings on mitochondria-driven NVU and BBB dysfunction, and how it might be studied in current and prospective NVU/BBB in vitro models for finding new approaches for the efficient pharmacotherapy of Alzheimer’s disease.

Early life stress (ELS) causes long-lasting changes in brain plasticity induced by the exposure to stress factors acting prenatally or in the early postnatal ontogenesis due to hyperactivation of hypothalamic-pituitary-adrenal axis and sympathetic nervous system, development of neuroinflammation, aberrant neurogenesis and angiogenesis, and significant alterations in brain metabolism that lead to neurological deficits and higher susceptibility to development of brain disorders later in the life. As a key component of complex pathogenesis, ELS-mediated changes in brain metabolism associate with development of mitochondrial dysfunction, loss of appropriate mitochondria quality control and mitochondrial dynamics, deregulation of metabolic reprogramming. These mechanisms are particularly critical for maintaining the pool and development of brain cells within neurogenic and angiogenic niches. In this review, we focus on brain mitochondria and energy metabolism related to tightly coupled neurogenic and angiogenic events in healthy and ELS-affected brain, and new opportunities to develop efficient therapeutic strategies aimed to restore brain metabolism and reduce ELS-induced impairments of brain plasticity.

The review contains data on the diversity of endogenous ligands of RAGE receptors (receptor for advanced glycation end products) that play an important role in the signal transduction in (patho) physiological conditions. RAGE takes part in various physiological

Background: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder. In recent years, attention of researchers has increasingly been focused on studying the role of brain insulin resistance (BIR) in the AD pathogenesis. Neuroinflammation makes a significant contribution to the BIR due to the activation of NLRP3 inflammasome. This study was devoted to the understanding of the potential therapeutic roles of the NLRP3 inflammasome in neurodegeneration occurring concomitant with BIR and its contribution to the progression of emotional disorders. Methods: To test the impact of innate immune signaling on the changes induced by Aβ1-42 injection, we analyzed animals carrying a genetic deletion of the Nlrp3 gene. Thus, we studied the role of NLRP3 inflammasomes in health and neurodegeneration in maintaining brain insulin signaling using behavioral, electrophysiological approaches, immunohistochemistry, ELISA and real-time PCR. Results: We revealed that NLRP3 inflammasomes are required for insulin-dependent glucose transport in the brain and memory consolidation. Conclusions NLRP3 knockout protects mice against the development of BIR: Taken together, our data reveal the protective role of Nlrp3 deletion in the regulation of fear memory and the development of Aβ-induced insulin resistance, providing a novel target for the clinical treatment of this disorder.

The review covers current concepts on cell and molecular mechanisms of neuroinflammation and aging with the special focus on the regulation of cytokine-producing activity of astroglial cells and intercellular communication. The review reflects that a key component of the aging phenomenon as a result of ineffective implementation of anti-inflammatory response are processes of the dysregulated cytokine production (Вестник РАМН. 2015; 1: 17-25) В течение последних лет существенным образом из-менились представления о клеточно-молекулярных механизмах воспаления [1]. Развитие воспаления свя-зано с локальной гиперпродукцией цитокинов, актива-цией рецепторов врожденного иммунитета, таких как Toll-подобные рецепторы (Toll-like receptors, TLRs), Nod-подобные рецепторы (Nod-like receptors, NLRs), скавенджер-рецепторы и другие, формированием ин-фламмасом, развитием окислительного стресса, измене-нием экспрессии про-и антивоспалительных цитокинов, а также молекул, вовлеченных в процессы межклеточных взаимодействий, активации клеток нейрональной и гли-альной природы, нейро-и ангиогенеза (интерлейкины, интерфероны, факторы роста, P2X7 рецепторы, CD 23, CD 38, CD 157, белки системы комплемента и их рецепто-ры, iNOS, COX 2, НАДФН-оксидаза и другие ферменты). Значительный прогресс достигнут в понимании механиз-мов развития иммунного ответа и системных реакций организма при воспалении, а также причин перехода вос-паления в хроническую форму [2,3].Активность иммунной системы и выраженность вос-палительной реакции, с одной стороны, определяют эф-фективность защиты организма от действия факторов, провоцирующих повреждение и дегенерацию, но, с дру-гой, могут стать важным механизмом старения. Прогрес-сирующая дегенерация при старении организма ассоции-рована со многими ключевыми признаками воспаления (окислительный стресс, повреждение клеток, дизрегуля-ция продукции цитокинов и пр.), поэтому неудивитель-но, что все большее внимание исследователей привле-кают механизмы, сопрягающие эти два процесса, в т.ч. в контексте развития так называемых возрастзависимых заболеваний. Появление термина «inflammaging» (воспа-ление и старение) в полной мере отражает эту тенденцию в определении исследовательских приоритетов [4]. Нейровоспаление: основные механизмы реализацииНейровоспаление -неотъемлемый компонент пато-генеза нейродегенерации, проявляющейся аксональной и синаптической дисфункцией, изменениями межкле-точных взаимодействий, деградацией макромолекул, на-рушениями метаболизма и развитием апоптоза. Хотя существуют представления о не столь однозначной со-пряженности процессов нейродегенерации и воспаления. Кроме того, нейровоспаление актуально и для развития заболеваний, в патогенезе которых долгое время не учи-тывали или не признавали воспалительный или иммун-ный механизмы (депрессия, аутизм, шизофрения) [5].

Alzheimer's disease is characterized by the loss of neurons, the accumulation of intracellular neurofibrillary tangles and extracellular amyloid plaques in the brain. However, there are contradicting data on differences in neurogenesis at the onset of the disease or before the formation of amyloid plaques. As awareness of the importance of the pre-symptom phase in neurodegenerative diseases grows in the context of early diagnosis and pathogenesis, we analyzed the critical periods of adult hippocampal neurogenesis at an early stage under the action of soluble Ab1-42 beta-amyloid. The proliferation, migration and neuronal cells survival were evaluated in mice with an injection of soluble amyloid beta-oligomers. It was found that the injection of Ab1-42 oligomers causes a decrease in cell proliferation in the mouse hippocampus. Despite the preservation of the neuroblast pool in animals after beta-amyloid injection, the process of radial migration is disrupted, and an increase in apoptosis in the neurogenic niche was revealed. Thus, our results demonstrate damage of neurogenesis critical stages: the progenitor cells, neuroblast migration, the integration of immature neurons, and the survival of neurons under application of soluble beta-amyloid oligomers. The obtained data indicate decline in proliferation rate in the subgranular zone, that is accompanied by ectopic differentiation and disturbed migration, producing, apparently, abnormal neurons that have lower survival rates. That could lead to a decrease in mature neurons numbers and the number of cells in the granular layer of the dentate gyrus.

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