Development of treatment methods for late-life cognitive disorders, understanding neuroimmune principles requires their consideration. The authors presented a descriptive review of 81 scientific publications on these topics.
The authors of this study suggest that neuroimmune mechanisms are of great importance in the pathogenesis of late-life cognitive disorders. They participate in the formation and maintenance of neuroinflammation.
One of the main features that the understanding of late-life cognitive disorders faces is its multifactorial nature of the mechanisms of their formation, structural and phenomenological diversity, due to the participation of molecular, macromolecular, cellular, neuroimmune, neurological and behavioral processes. Neuroimmune mechanisms in the development of late-life cognitive disorders do not simply reflect the classification of neurodegenerative diseases, they also provide fundamental insight into the etiology and pathogenesis, since they suggest a central role in the initiation of the disease and subsequent progression. Based on a systematic assessment of the literature, this study identified the dysfunction of the neuroimmune system, defining the understanding of neuroinflammation as a mechanism for the formation of neurodegeneration in late-life cognitive disorders through the activation of microglia, the release of provocative cytokines.
The aim of our work is to review scientific publications that examine the involvement of neuroimmune factors in the development of cognitive disorders in late life.
The study materials are presented by publications included in PubMed - an electronic library, a search engine for biomedical literature and eLIBRARY. Each publication was selected using manual search. The depth of the literature search is 10 years. A synthesis of information obtained from the selected sources was carried out. The results of the synthesis of objects are presented in structured text, indicators and tables. Searching by keyword combinations increases the efficiency of publication selection, we conducted a descriptive review of 81 scientific publications. The review included publications that met the inclusion criteria
Inclusion criteria:
The concept of involvement of neuroimmune mechanisms in the development of cognitive disorders in late age.
Developing treatments for late-life cognitive disorders, understanding neuroimmune principles requires their consideration. As the prevalence of cognitive dysfunction continues to increase [1,2], identifying early risk factors is critical for identifying and treating late-life cognitive disorders [3]. According to G.Davies et al. (2018), cognitive function is not as easily measured as, say, height, and is far from standardized, although it is possible to apply a dimensional approach [4, 5].
Cognitive disorders are heterogeneous conditions that arise in neurological, somatic and pain diseases. The main causes in old age are various neurodegenerative, cerebrovascular diseases and dysmetabolic disorders, various somatic dysfunctions [6]. Genetic, environmental and behavioral factors together predispose to cognitive disorders, and many biological pathways are involved in this regard, including neuroinflammation, mitochondrial dysfunction and blood-brain barrier disorders [1,7].
Late cognitive disorders are an important modern problem that has a huge impact on the lives of patients, disrupting social and professional functioning [8,9]. The methods of early diagnosis of cognitive disorders are magnetic resonance imaging, positron emission tomography (PET) with fluorodeoxyglucose, PET with amyloid, PET with tau [10, 11], as well as cerebrospinal fluid analysis. However, their use is limited due to high cost, complexity of implementation and invasiveness. Therefore, the search for other informative biomarkers available in clinical practice is a priority task of modern research. The availability and minimally invasiveness of laboratory blood tests meets the requirements of early diagnosis and large-scale prescreening or screening of cognitive disorders in accordance with other research methods [12,13].
Traditionally, Alzheimer's disease was considered a proteopathy caused by misfolding and oligomerization of β-amyloid and tau. Today, it is generally recognized that amyloid deposits and neurofibrillary tangles, as well as their precursors and metabolites, poorly correlate with the cognitive stage of the disease and, thus, have low diagnostic or prognostic value [14]. In this regard, immunopathy becomes the leading factor [15, 16, 17, 18, 19]. The results of genetic studies indicate the involvement of the immune system in the pathogenesis of neuropathological changes in Alzheimer's disease, causing dementia [20,21]
The study of the immune system of the brain in people with neurodegenerative diseases has advanced rapidly over the past 2 decades [22].
The authors analyzed scientific works studying neurodegenerative signs of brain aging. Despite the noticeable similarity in etiology at both the cellular and molecular levels. The following distinctive features were identified (Table 1):
Table 1.
Signs of neurodegenerative diseases
|
Taylor J.P., et al[24]. Ling S.C.,et al[25]. |
2016 2013
|
Damage to RNA and DNA |
|
KaushikSetal[26]. |
2015 |
Disrupted proteostasis |
|
Ransohoff R.M et al[27]. |
2016 |
Metabolic changes in neuroimmune cells that lead to morphological changes in glial cells and the microenvironment of the neuroimmune system. |
|
Barnham K.J et al [28]. Hetz C et al[29]. |
2004 2017 |
Oxidative stress and endoplasmic reticulum stress |
|
Richards R.I., et al [30]. |
2018 |
A chronic condition that has traditionally been viewed as a protective function of the body but is now recognized as a hallmark of neurodegenerative diseases. Chronic conditions can result in focal top cell death as a containment strategy, limiting the ability of pathogens and oncogenic cells to divide and spread. |
|
JorfiM. et al[31]. |
2023 |
A dramatic increase in T cell and monocyte infiltration is selective in Alzheimer's disease. CD8+ T cell infiltration leads to increased microglial activation and worsening neuroinflammation and neurodegeneration. |
|
Zeng J et al[32]. |
2024 |
Aging, as a major risk factor for Alzheimer's disease, markedly alters the number and subtypes of T cells, affects BBB function, and changes the brain microenvironment. |
Neurodegenerative disease has several main principles, the most significant of which is neuroinflammation [33, 34, 35]. Neuroinflammation is a characteristic feature of the brain of people dying from dementia [36, 37]. Neuroinflammation, constantly activated in the activation of microglia and astrocytes, which leads to an increase in the formation of proliferative cytokines and reactive oxygen species, is one of the main principles causing flexible neurons. Although traditionally considered to be almost exclusively a late stage of disease pathogenesis, modern studies show that it can also be an early stage [38, 39, 40, 41].
The authors analyzed articles studying the neuroimmune system (Table 2)
Table 2.Neuroimmune system
|
Microglia |
1. Immune cells located in the central nervous system, responsible for central nervous system immune surveillance, regulation of neuronal activity, synaptic maintenance and plasticity [42]. Microglia are dynamic cells that continuously promote self-remodeling and can attack neurons exposed to stress [43]. They play an active role in the central nervous system immune response by producing pro-inflammatory and anti-inflammatory cytokines (microglia subtypes M1 and M2) [44]. |
|
Astrocytes |
They participate in physiological and pathological processes in the central nervous system [45]. These processes include not only interruptions and fast synapses [46], but also maintenance, pruning and remodeling of synaptic transmission and plasticity [47]. Astrocytes are able to influence several neurotrophic factors that promote differentiation and survival of neurons [48,49]. They regulate the restoration of the nervous system by controlling biochemical processes in the epithelial cells of the blood-brain barrier (BBB) and activate the processes of repair and scarring after the innate immune response [50]. |
|
Oligodendrocytes |
Provide support, protection and growth of axons [51]. |
Recognizing that the neuroimmune system operates as a complex, interconnected network of cells and signaling pathways that are critical for maintaining nervous system homeostasis, it is clear that disturbances in these components are major contributors to the development of cognitive disorders [44,52, 53].
Neuroimmune disorders provide additional heterogeneity in the etiology and neuropathogenicity of cognitive disorders. Thus, neuroimmune interactions are increasingly becoming a major focus of research in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis [54]. Crosstalk between the brain and the peripheral immune system occurs sequentially either through the blood-brain barrier [55], the choroid plexus [56,57], or through brain circuits [58-60]. Current research suggests that all of these parts of the brain undergo structural and/or biological changes during aging and Alzheimer's disease and may act as gateways for peripheral immune cells to enter the brain. Immunoprofiling studies have shown heterogeneity in microglia [61, 62, 63] and peripheral immune cells including myeloid cells [64], T cells [65, 66] and B cells [60, 67] in Alzheimer's disease. Recent studies have also begun to elucidate the role of peripheral immune cells in brain health and neurodegenerative diseases. However, research into the role of peripheral immune cells in the human brain, which varies across organisms, is still in its early stages. Given the compelling recent evidence implicating the peripheral immune system in the pathogenesis of Alzheimer's disease, future studies are ultimately needed to fully understand the contribution of genetics associated with peripheral immune cell infiltration into the brain to brain health and neurodegenerative diseases [68].
The authors reviewed the literature on the impact of the peripheral immune system on cognitive impairment in late life. The data presented provide new insights into the contribution of the peripheral immune system to the pathology of cognitive impairment.
Zeng J. et al. [32] It was noted that T cells interact with key factors such as Aβ and Tau proteins in the pathological background of Alzheimer's disease, triggering inflammatory processes that cause neuronal degeneration, ultimately affecting cognitive function.
Bachstetter A.D. et al. [23] Decreased levels of T H 17 cytokines produced by activated T cells were found in women with early cognitive decline, which the authors suggested indicates a systemic immunological stage associated with dementia and with the directions of circulating CD4+ and CD8+ T cells, as well as concentrations of glial fibrillary acidic protein and light neurofilaments.
Unger M.S. et al. [69] concluded in their study that CD8+ T cells begin to penetrate the brain in Alzheimer's disease, and new cellular players emerge that control neuronal and synaptic changes. Understanding the precise functional innovations of the CD8+ T cell subset in the brain of patients with Alzheimer's disease may open up new avenues for treatment by modulating the immune system. According to Grayson G.M. et al., study participants with positive amyloid status and mild cognitive impairment had increased numbers of differentiated T cells, myeloid, and plasmacytoid dendritic cells in the blood [70].
In their study, HuizeC. et al. considered that microglia, astrocytes, macrophages, mast cells and T cells are involved in the pathogenesis of Alzheimer's disease through neuroimmune mechanisms and inflammatory processes [33]. on the imbalance of the immune response in the preclinical stages of Alzheimer's disease [71].
In recent years, strong evidence has emerged that immune system dysfunction is a fundamental feature of the pathogenesis and progression of Alzheimer's disease [72]. More importantly, not only the CNS immune process but also the peripheral immune system are altered and interact with the central immune response in Alzheimer's dementia [73]. Thus, a comprehensive analysis of the peripheral immune cell abundance and coordination with the central immune system in Alzheimer's disease, especially at the stage of minimal cognitive decline, provides a deeper understanding of the role of the immune system in the development and progression of the disease and creates a new target for the early diagnosis and treatment of cognitive disorders. 74].
The study of the mechanism of pathogenesis of cognitive disorders in old age by modern researchers comes to the conclusion that the manifestations of diseases are the result of the interaction of two opposing processes: the traditionally widely studied neurodegeneration and the structure of brain restoration [75,76,77].
It is important to recognize that the pathology of Alzheimer's disease begins a decade or more before the onset of cognitive decline. However, the various therapeutics that target the presymptomatic "initiating" mechanisms of abnormal proteostasis—β-amyloid aggregation and deposition and p-Tau induction by Aβ oligomers—are most often administered at symptom onset, when neuroinflammation has already inundated the affected brain regions. As such therapeutics targeting the proteinopathy associated with Alzheimer's disease fail to improve cognitive symptoms and signs to any significant degree, they are best administered when the pathology of β-amyloid plaques and tangles and glial activation first begins, typically a decade or more before symptoms, in a prophylactic or secondary prevention manner. Human resilient brains, which exhibit abundant levels of plaques and/or tangles in the absence of cognitive changes at death, have shown that accelerated neurodegeneration leading to clinical dementia is preceded by neuroinflammation, microglial activation, release of provocative cytokines and reactive astrocytes [78].
The main question that now remains to be answered is whether therapies that target neuroinflammation and neurodegeneration due to neuroinflammation will be more successful in effectively managing the symptoms of Alzheimer's disease than those that target abnormal proteostasis—plaques and tangles—which may be better suited for prevention. Ultimately, successful implementation of interdisciplinary research among experts with disparate and complementary areas of expertise in neuroscience (including computational neuroscience), genetics, immunology, neuroscience, and bioengineering will be necessary to generate a challenging paradigm, a challenge for the successful development of therapies aimed at altering, halting, or reversing the neuroimmunopathogenesis of cognitive disorders [79].
Klinkovsky A. et al. 2023 [80] notes that current methods of treating cognitive disorders, despite their effectiveness in slowing down neurodegeneration, do not use the underlying cause, which is the gradual loss of neurons. Therefore, the search for new treatments is crucial. The advent of gene therapy and other innovative treatments provides improved treatment outcomes and quality of life for patients. However, in some cases, it is important to gain a full understanding of the fundamental mechanisms underlying late cognitive decline and recognize their distinctive characteristics before developing new interventions. By targeting the distinctive features of neurodegenerative diseases, it is possible to develop treatments that use the underlying cause of the disease, not just its symptoms.
Prospects of modern research and neuroimmune studies in the fight against cognitive disorders of late age.
Understanding the role of the immune system in neurodegenerative diseases has undergone dramatic changes over time. Neuroimmune interactions have come a long way to occupy a central position in the study of late-life cognitive disorders. Despite significant advances in recent years, fundamental questions remain unanswered, with conflicting data regarding immune overactivation, maladaptation, or attrition in neurodegenerative diseases. [81] Thus, promising research directions in developing a neuroimmune concept of late-life cognitive disorders include:
This review may be of interest to specialists in the field of neuroscience and mental health.
The authors of this study suggest that neuroimmune mechanisms in the pathogenesis of late-life cognitive disorders are of great importance, as they provide insight into the neuronal hypothesis and provide insight into the role of novel neuroinflammation in multiple cognitive disorders. A path to a better understanding of the role of the immune system in the pathogenesis of late-life cognitive disorders, with the hope of more effective methods in the future.
Acknowledgments
The authors express their deep gratitude to the researchers whose scientific works were cited in the review and analysis.
Conflict of interest
The authors have no conflicting interests related to this study.
Financial support
The authors reported that this study received no financial support.
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