The brain has its own innate immunity that senses the surrounding brain structures and intervenes quickly in order to deal with any emergency or invaders ^[1][94].

It also responds to changes so as to restore order and re-establish parenchymal homoeostasis ^[2][95].

Physiologically, the brain has a unique immune system, a belief that was reinforced by the discovery of microglia cells ^[3][96].

Microglia are the primary innate cells of the central nervous system (CNS) and the most predominant immune cells, which account for 80% of the brain immune cells and represent 10–15% ^[4][97] of all cells found within the brain. The microglia were discovered by the Spanish neuroscientist Pío del Río-Hortega in 1919, meaning that, in 2022, 103 years had passed since their discovery ^[5][98].

While he proposed that these cells arise from meningeal macrophages and penetrate the brain during embryonic development, many researchers, including Río-Hortega, supposed that the brain microglia may also originate from bone-marrow-derived monocytes ^[6][99].

However, it is now established that the microglia originate from a unique stem cell type in the yolk sac and join the CNS during embryonic creation, and they proliferate and dissipate in a non-heterogeneous manner within the CNS ^[7][100].

Microglia are a type of neuroglia (glial cell) resident to the CNS that are highly dynamic, moving constantly so as to actively survey the brain parenchyma ^[8][9][46,101].

Microglia present various morphological features dependent on their specific anatomical or activation profile ^[10][11][12][51,102,103], such as the lysosome content ^[13][104], membrane composition ^[14][105], electrophysiological activities (i.e., hyperpolarized resting potentials and differential membrane capacitance) ^[15][106] and gene transcriptome profile ^[16][17][107,108].

The microglia regulate brain development, brain maturation and homeostasis, initially, through two pathways: the secretion of diffusible factors and phagocytosis activity ^[18][37].

The microglia become activated following exposure to exogenous attacks and/or endogenous brain damage, and then, by a clearance mechanism, they phagocytize many elements in the brain, including synaptic elements, living cells, dead cells, bacteria and axons ^[19][20][21][109,110,111].

Macroglia, as the first line of defense and the cornerstone of the natural immunity of the CNS, also contribute to acquired immunity through their interaction with CD4⁺/helper and CD8⁺/cytotoxic lymphocytes, which enter the CNS during chronic infection or inflammation ^[22][112].

It is understood that the interactions and cohesion between innate immunity and acquired immunity can lead to the resolution of infections, neurodegenerative events or neural repair, depending on the context ^[23][113].

Presumably, chronic inflammation, in the context of a long-lasting infection that lasts for a prolonged time, without fail can destroy healthy brain cells. Indeed, when neuroinflammation is not settled, the effectiveness of the immune system decreases dramatically, which leads to adverse results, leading in turn to harmful consequences, contributing to the alteration in the brain health status and neuronal loss, which is considered to be at the forefront of the causes of neurodegenerative disorders ^[24][25][114,115].

Therefore, neuro-inflammation and uncontrolled inflammation provoked by both the microglia and lymphocytes are implicated in neurodegenerative diseases, especially Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis ^[26][116].

Astrocytes are a specialized sub-type of glial cells that exceed the neuron number by over five-fold ^[27][117]. They are the most numerous brain cells, which contiguously tile the entire CNS ^[28][118].

The proportion of astrocytes in the brain varies by brain region and ranges from 20% to 40% of all glial cells. Astrocytes perform plenty of essential and complex functions in the healthy and unhealthy CNS ^[29][119]. Their functions encompass a regulatory role, supporting the nutrition activity of the neurons, and they are implicated in neurogenesis and synaptogenesis, providing biological and chemical support to the endothelial cells of the blood–brain barrier (BBB), controlling BBB permeability and maintaining extracellular homeostasis ^[30][120].

Astrocytes’ function goes beyond the regulation of blood perfusion. They also transport mitochondria to the neurons and intervene in the building blocks of neurotransmitters ^[31][121].

In addition, astrocytes can phagocytose synapses, alter the neurotrophin release, contribute to the clearance of β-amyloid proteins (Aβ) and limit brain inflammation and clear debris ^[32][33][122,123].

The activation (or reactivation) of astrocytes is implicated in neurological diseases, as it defines the progression and the outcome of neuropathological process ^[34][35][124,125].

In fact, in response to many CNS pathologies, such as stroke, infections, inflammation, trauma, tumorigenesis, Parkinson’s disease and epilepsy, they cause damage to the vascular system, provoking BBB impairment and oligemia, which ultimately correlate with dementia and neurodegenerative diseases ^[35][125].

Abnormal functions of the astrocytes have been illustrated in AD patients in vitro and animal models in vivo ^[36][37][126,127].

Magistretti and Pellerin (1999) ^[36][126] and Magistretti (2006) ^[37][127] described the metabolic cooperation between astrocytes and neural cells. They concluded that this collaboration is important for the brain’s functioning. In their studies both in vivo and in vitro, they indicated that astrocytes play essential roles in the regulation and control of the cerebral blood flow according to the neuronal activity and metabolic demands. Therefore, astrocytes play a cardinal role in guaranteeing an adequate coupling between the brain activity and metabolic supply. The neurons’ metabolism and the energy required for the neurons to function depend on the blood oxygen supply but also on astrocytic glucose transporters, mainly glucose transporter 1 (GLUT1), a trans-membrane protein responsible for facilitating the diffusion of glucose across a membrane ^[38][128]. In addition, astrocytes have the ability to convert glycogen to lactate during periods of higher activity of the nervous system ^[38][128]. Plenty of studies have shown a notably reduced cerebral glucose metabolism in mild AD and its correlation with symptom severity ^[39][40][41][129,130,131]. It is well known that Aβ affects neuronal excitability and may reduce the astrocytic glycolytic capacity ^[42][43][132,133] and diminish the neurovascular unit function ^[44][45][134,135]. In addition, reductions in the GLUT1 and lactate transporters in astrocyte cultures derived from transgenic AD mice have been reported ^[46][136]. Thus, in AD, the resulting metabolic compromise may alter the overall oxidative neuronal microenvironment. The long-standing effect of a diminished lactate supply, decreased neuronal activity and reduced neurovascular coupling underlines the oxidative stress and accelerates the development of AD. Therefore, astrocyte dysfunction leads to neural damage and neurodegeneration ^[47][48][137,138].

The overproduction and accumulation of amyloid beta (Aβ) senile plaques in the vessel walls and aggregation of the tau protein in neural cells, which are the hallmarks of AD, have been shown to hinder neurotransmitter uptake and gliotransmission and disturb calcium signaling in the astrocytes ^[49][139].

Thus, astrocyte dysfunction makes matters worse by releasing toxins and altering the basic metabolic pathways, which can accelerate neurodegeneration ^[47][137].

Astrocytes and microglia frequently intersect. They have been shown to have similar functional properties, and both are implicated in neurodegenerative diseases, such as those following neuroinflammation. Astrocytes release chemokines that convert the microglia and macrophages to a more pro-inflammatory phenotype ^[50][140], and this process triggers the leakage of peripheral immune cells, formation of edema and enhanced BBB permeability due to the breakdown of its barrier. Otherwise, they differ significantly from a structural perspective, since they have different developmental origins. They are derived from neuro-epithelial progenitors, whereas microglia are derived from a common hematopoietic myeloid progenitor that enters the brain during embryonic development ^[51][141].

Indeed, astrocytes are considered crucial regulators of innate and adaptive immune responses in the injured CNS ^[52][53][54][142,143,144].

In AD, as in the case of other brain disorders, the active neuroinflammatory involvement of the astrocytes can be observed ^[48][138].

Indeed, the deficiency in the astrocytes’ function as a result of cellular senescence can have great consequences on, and implications for, neurodegenerative disorders, such as AD and Huntington’s disease, and for the aging brain ^[55][56][145,146].

A profound decline in acquired immunity, compared to the innate immunity response, has been observed in aging brains ^[57][147].

The stem cell hematopoietic (HSC) pool decreases with age and varies throughout the production of myeloid cells ^[58][148]. The decreasing mechanism of the T cells during aging continues with lymphopoiesis and the decrease in the thymic lymphoid progenitors, leading decreasing T cell generation ^[59][149]. In complex and systematic diseases, such as AD, it appears that some of the dysregulation found in the brain is present in the peripheral immune systems ^[60][61][150,151]. Many disturbances in the activity of the B and T lymphocytes have been described in AD, such as changes in the T cell clonality. It seems that there is a shift towards a CD4 response over a CD8 response in AD, and usually there is an enhanced susceptibility to death caused by hydrogen peroxide (H₂O₂) ^[62][152].

With respect to the changes in the T lymphocyte profile, depending on the severity of the disease ^[63][153], it was observed that there is an increase in the pro-inflammatory factors (amyloid beta (Aβ) and tau protein (tubulin-associated)) in moderate and severe AD. Disequilibrium between the effector T cells that release IL17 or interferons and the T lymphocytes reg leads to a decrease in neuroprotection and irreversible neuron death and neurodegeneration ^[64][65][67,154].

The term “cytokines” was first coined by the pathologist Stanley Cohen in 1974 ^[66][155]. Kenneth Murphy and Casey Weaver, in 2017, described the cytokines as a broad stratum of small proteins (~5–25 kDa) ^[67][156] that are necessary for cell signaling and critical for monitoring the growth and activity of immune cells, blood cells and additional blood cells that help the body’s immune, and that they are the key modulators of inflammation secreted in response to invading pathogens so as to stimulate, recruit and proliferate immune cells ^[68][69][157,158].

The dominant producers of cytokines are the helper T cells (Th) and macrophages. These cells can be produced by polymorphonuclear leukocytes (PMN), endothelial and epithelial cells, adipocytes and connective tissue ^[69][70][158,159].

The physiological and pathological production of cytokines take place in and through the peripheral nerve tissue, regulated by resident and recruited macrophages, mast cells, endothelial cells and Schwann cells ^[71][160].

Thus, cytokines are important in health and disease and are secreted in response to pathogens so as to stimulate, recruit and proliferate immune cells, specifically in the context of host immune responses to infection, inflammation, trauma, sepsis, cancer and reproduction ^[72][161]. Today, five different types of cytokines have been found in the body: chemokines, interferons, interleukins, lymphokines and tumor necrosis factor (TNF) ^[73][162].

These cytokines’ essential activities are cell growth, cell differentiation, cell death and cell signal transduction. In addition, the majority of cytokines intervene in the inflammatory response and act as anti-inflammatory agents ^[74][75][163,164].

It is worth mentioning that the main cytokines involved in the adaptive immune system include IL-2, IL-4, IL-5, TGF-β, IL-10 and IFN-γ ^[76][165].

One important type of cytokine family are the chemokines, small peptides that bind to heparin and are chemo-attractants. Several are pro-inflammatory chemokines, and together, they and their receptors, represented by MCP-1 (chemokines—C-C motif) ligand 2 (CCL2) and its receptor (CCR2), are considered as biomarkers that can be used to evaluate AD progression, since the progression of AD seems to be related to the expression of chemokines ^[77][166]. MCP-1 is over-expressed in the neurotic plaques of AD patients, and the high-CSF tertile of MCP-1 represents a more progressive cognitive deficit compared to those with the lowest MCP-1 tertiles ^[78][167].

Additionally, in AD condition, chemokines (CCL5—RANTES) regulate the expression and secretion of T cells, representing the most widely studies sub-type ^[79][168].

High levels of CCL5 of astro-glial origin have been observed in the cerebral micro-circulatory framework of the brain parenchyma of AD patients, resulting in an increase in the reactive oxygen species, a process mediated by cytokines ^[80][81][169,170]. In fact, immunosenescence is a dysregulation of the immune system that accompanies aging ^[80][81][169,170].

Monocytes and macrophages are, in essence, cells of the innate immune system, and they play a crucial role in tissue homeostasis. Due to their plasticity and diversity, they are considered to be hallmarks of the monocyte–macrophage differentiation pathway ^{[82][83][84][85][86]}[171,172,173,174,175]. Their focal tasks in the onset and settling of inflammation are pivotal. Thus, via their involvement in the phagocytosis process, through defending the body from various invaders, the secretion of cytokines and reactive oxygen species (ROS) and, finally, the stimulation of the acquired immune system, they play crucial roles in the immune system. Indeed, immune cells, especially the macrophages, have a heterogeneous activity within the pathological CNS. In addition to their phagocytic ability, macrophages produce neurotropic factors, enhance neuroinflammation induction and resolution, increase angiogenesis and regeneration and play a role in cell replacement, as well as the control of matrix remodeling ^[87][88][89][176,177,178]. The origins of both cells come from the same myeloid precursor, while each has a different life span. Macrophages, compared to monocytes, have a long-life span, while monocytes have a shorter life span and undergo unrestrained apoptosis on a daily basis ^[90][179]. In long-standing inflammatory illnesses and in the malignancy microenvironment, the inhibition of the apoptotic mechanism was observed, leading to an increase in the monocytes’ survival, which eliminated their apoptotic destination through their differentiation into macrophages ^[91][180]. Thus, the suppression of the apoptotic program and stimulation of a strong survival pathway are the underlying mechanisms that determine the monocyte/macrophage lifespan. This enhances the accumulation of the macrophages and leads to the extension of an inflammatory response ^[92][181]. However, when the inflammation is resolved, the return to a survival program is suddenly halted, and apoptosis begins again. Notwithstanding the fact that aging is a physiological phenomenon, it is a worldwide burden, in which all body systems cease to function appropriately. Infections, chronic low-grade inflammation (inflammaging), neuropsychiatric disorders, malignancy and reductions in vaccine efficacy all accompany aging. This may partially be attributed to the decline in adaptive immunity, termed immunosenescence, where the rate of morbidity also increases dramatically. Thus, inflammation is the engine of morbidity and mortality, while chronic inflammation is known to be harmful to the activity and function of the immune system. Monocytes and macrophages are the central cells which are believed to support the inflammaging phenomenon. Their activity deteriorates with age. The impact of aging on these cells is clear, and it is determinantal, accompanied by a diminished phagocytosis rate and immune resolution, enhanced inflammatory cytokine production and decreased autophagy. This picture stresses the involvement of the monocytes and macrophages in the immunosenescence and inflammaging phenomena, and the outcomes have a crucial role in the dysfunction of the immune system with increasing age ^[93][182].

The brain possesses an immune-privileged autonomous system, which is supported by its own phagocyte immune cells and the local microglia ^{[1][94][95][96][97][98][99]}[94,183,184,185,186,187,188].

It is well known that the relationship and the connection between the brain–immune system and the peripheral immune system is complicated.

In the case of pathological events or neuroinflammation, such as a demyelinating disease (multiple sclerosis), neurodegenerative diseases (such as AD) or autoimmune inflammatory illness, the infiltration of the CNS by blood-derived immune cells as a response to a brain injury has catastrophic consequences. According to dogma, this infiltration of the immune cells, predominantly the monocytes/macrophages, has been viewed as a strange event, with neuro-destructive consequences for the brain tissues. For instance, neuroinflammation constitutes an essential feature of AD, wherein the innate immune cells are the first natural protector of the brain in the presence of neurotoxic molecules, such as amyloid plaques (Aβ). This front-line natural defense system seems inadequate in AD patients ^[100][189].

In AD patients, the activation of the microglia due to the formation of Aβ causes extensive damage to the brain. The fact that monocytes/leukocytes provoke neural dysfunction in diseases that are characterized by dysregulated innate immunity and cognitive dysfunction is explained by the fact that monocytes/macrophages and monocyte-derived cells are unable to clean neurotoxic materials from the brain, and through their interplay with astrocytes at the periphery–brain interfaces, they modify synapse development and plasticity, or they can penetrate the CNS to exacerbate neuroinflammation. It is believed that the neuroinflammation observed in AD is exclusively linked to Aβ ^[101][190].

Nevertheless, in recent years, researchers have stressed the potential collaboration between systemic and local mild chronic inflammation in instigating the neurodegenerative cascade observed in AD ^[102][103][191,192].

All these cellular events increase houman'sr sense that the monocytes/macrophages and other peripheral immune cells are deeply involved in brain functioning and participate in behavioral and cognitive impairment. The research on neuroinflammation in AD is still contradictory, and many studies have shown paradoxical results about the advantages and disadvantages of neuroinflammation ^[104][193]. According to one opinion, neuroinflammation has neuroprotective effects and plays a crucial protective role in the brain. On the other hand, it causes neurotoxic effects by triggering the inflammatory response ^{[87][105][106][107][108]}[176,194,195,196,197].