Microglial Turnover in Ageing-Related Neurodegeneration: Therapeutic Avenue To Intervene in Disease Progression Part 1

Abstract

Microglia are brain-dwelling macrophages and major parts of the neuroimmune system that broadly contribute to brain development, homeostasis, aging, and injury repair in the central nervous system (CNS). Apart from other brain macrophages, they can constantly sense changes in the brain’s microenvironment, functioning as housekeepers for neuronal well-being and providing neuroprotection in normal physiology. Microglia use a set of genes for these functions that involve proinflammatory cytokines. In response to specific stimuli, they release these proinflammatory cytokines, which can damage and kill neurons via neuroinflammation. However, alterations in microglial functioning are common pathophysiology in age-related neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s, and prion diseases, as well as amyotrophic lateral sclerosis, frontotemporal dementia, and chronic traumatic encephalopathy. When their sentinel or housekeeping functions are severely disrupted, they aggravate neuropathological conditions by overstimulating their defensive function and through neuroinflammation. Several pathways are involved in microglial functioning, including the Trem2, Cx3cr1, and progranulin pathways, which keep the microglial inflammatory response under control and promote clearance of injurious stimuli. Over time, an imbalance in this system leads to protective microglia becoming detrimental, initiating or exacerbating neurodegeneration. Correcting such imbalances might be a potential mode of therapeutic intervention in neurodegenerative diseases.

Keywords

microglia; neurodegeneration; neuroinflammation; macrophages; homeostasis; Cistanche benefits.

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Introduction

Microglia are brain-dwelling parenchymal macrophages [1] that are distinct from other brain-dwelling non-parenchymal macrophagic populations and tissue macrophages [2,3]. Under healthy and normal conditions, microglia are self-maintained with no considerable contribution of peripheral myeloid cells [4]. In addition, ~5% of the total cells of the neocortex are normally microglial [5]. These macrophages have a uniform distribution throughout the central nervous system (CNS) parenchyma, with a population of approximately 10% of the total cells in the CNS. In addition, they can form a cellular grid with their ramified and highly motile process [6]. During the developmental phase of the brain, microglia help shape neural circuits by modulating the strength of synaptic transmissions and sculpting neuronal synapses. When sensing any CNS injury, they become phagocytic and eliminate microbes, cell debris, protein aggregates, or any form of CNS insult. However, microglial activation has been reported during several neurological conditions [7,8], in which they have been playing both beneficial and detrimental roles, depending on disease progression.

The correct functioning of microglia is necessary for neural circuit remodeling and synaptic function, but their involvement in the pathogenesis of neurological diseases raises the debate of whether microglial activation is beneficial or detrimental. In response to CNS insults, microglia proliferate rapidly [9], but their proliferation and turnover rates under homeostatic conditions have not been well documented. Filling this research gap could differentiate them from disease-causing agents [10]. Several studies have shown interesting but conflicting results, either very low or very high microglial turnover in mice and the post-mortem brain [11–13], although the validity of these techniques has been arguable and limited [14,15]. However, understanding the regulation of microglial populations in the brain is crucial to understanding their functioning at different phases of age and age-related diseases. In one case, the mouse model of AD showed that early priming of individual microglia can induce long-lasting functional changes in life, whereas microglial senescence may have a role in age-related neurodegeneration [10]. For example, stimulation of the brain’s immune system during development can induce long-lasting changes in microglial immune responses [16,17], and aging and senescence of microglia contribute to neurodegenerative disorders [18].

However, changes in microglial homeostasis and functioning during age and age-related neurodegenerative diseases could be due to alterations in the brain’s microenvironment or to the longevity of microglia, possibilities that remain unclear. Therefore, this article will discuss in detail microglia’s physiological role and changes due to exposure to different insults in individual age-related neurodegeneration.

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Molecular and Functional Background of Microglia

Microglia are the resident immune cells of the brain and cover almost 5–12% of CNS cells [19]. In addition, microglia are involved in the homeostasis of host defense against pathogens and consequent neurological disorders [20,21]. These cells are mesenchymal, originating in the yolk sac, and do not require hematopoietic stem cells for renewal [13,22]. Their survival and maintenance depend on cytokines, including CSF1 and interleukin (IL)-34 [23], and on transcription factors such as IRF8 [22]. However, microglia can be simply defined as innate immune cells of the CNS that originate from myeloid cells and express several genes, including Cx3cr1, CD11b, Iba1, and F4/80 [21]. Depending on comprehensive knowledge of microglial gene expression and relevant functions [21,24], this study attempted to determine microglial functions by their gene expressions. There are three basic functions of microglia—sensing their environment, maintaining physiological homeostasis, and protecting against self-modified and exogenous injurious agents. Furthermore, these normal functions are important regulators from a human being’s embryonic stages through to old age.

Sensing is the primary requirement for microglia to function in housekeeping and defending their host from injury (Figure 1). Microglia form a network that spans throughout the CNS. Their thin processes are dynamic and in constant motion, allowing them to scan the area surrounding their cell body every few hours and rapidly polarise toward focal injury [8,19]. This network includes approximately 100 or more genes that consistently scan surrounding cell bodies and sense any changes in their microenvironment [24–26]. The sense mRNA is expressed uniformly in microglia of different regions of the brain, indicating that all microglia are capable of sensing functions.

The second and most important part of the microglial function is physiological homeostasis. This function includes synaptic remodelings such as CNS development and maintenance, neurodegeneration [27,28], phagocytosis of dead or malfunctioning neuronal cells or cell debris [29,30], or myelin homeostasis [31] (Figure 2). In addition, microglia activate several inflammatory pathways that cause neuroinflammation and possibly neurodegeneration. In this process, microglia interact with astrocytes, and their interaction is also important in regulating homeostasis. Several chemokine and chemoattractant housekeeping genes are involved in phagocytosis (Trem2), synaptic pruning, and remodeling (C1q and Cx3cr1) [24], and anomalies in these housekeeping genes may lead to neurodegeneration.

As carriers of innate immunity, microglia defend their host against pathogens (Figure 1)injurious proteins including Ap, aggregated a-synuclein, mutant huntingtin (mHtt), mutation (mPrp^Sc), and oxidized superoxide dismutase (SOD). Microglia activate several receptors to incite host defenses, such as expressing Fc receptors, Toll-like receptors (TLRs), and several antimicrobial peptides including Camp and Ngp (24]. Therefore, microglia approach the neuroinflammatory threshold by producing peripheral inflammatory cytokines such as TNF-a and IL-1 (33 34). In addition, this process involves chemokines (e.g., Ccl2that recruit additional cells and work together to clear pathogens and normalize the brain in a homeostatic condition (35]. However, consistent microglia-induced neuroinflammation leads to neurotoxicity and, eventually neurodegeneration. In contrast to the anomalies in this microglial functioning, healthy neural microglia are always actively functioning through sensing, housekeeping, and protecting their host.

Microglia and Ageing

Aging is inevitable, and several structural and functional changes occur in the brain with advanced aging. For instance, the brain loses a total mass of about 2 to 3% per decade after the age of 50. This loss of mass with age specifically affects the volume of grey and white matter in the prefrontal, parietal, and temporal areas (36-38]. Therefore. an individual gradually loses complex learning abilities and declines in cognitive function (38,39]. Several cellular-level changes also occur in aging brains, such as genomic instability, shortening of telomeres and activation of tumor suppressor genes, protein mutation and accumulation, oxidative stress, reduced autophagy, and mild to chronic inflammation. It is imperative to maintain the balance between pro- and anti-inflammatory cytokines. However, a brain undergoing advanced aging shows an imbalance between these cytokine levels in response to chronic exposure to physical, chemical, or biological agents, such as ionic radiation, pollutants, and pathogens (40,41]. Studies have shown that chronic exposure to endogenous or exogenous pathogens decreases the anti-inflammatory cytokine IL-10 (42. In contrast, such exposure also increases inflammatory cytokines such as TNF-a and IL-1 in the CNS (43] and IL-6 in plasma (44. Additionally, increased systemic inflammation causes neuronal cell death and an imbalance between clearance and production of ROS, severely damaging synaptic plasticity as well (Figures 2 and 3). Many of these alterations in aging brains include impairment in basal autophagy that begins with cellular stress. Aging human brain analysis has shown a reduction in autophagy genes, including Atg5, Atg7, and Becn1 (45], and similar downregulation in Atg-proteins has been evident in aging mouse brains. In contrast, aging has been found to upregulate mTORC1 (45,46] and accelerated mTOR reduces macroautophagy and promotes aggregated protein and metabolic disturbances during aging. These data have been supported by the rapid development of neurodegeneration in Atg5- [47] and Atg7- depleted (48)mice. Microglia, as the first line of host defense, selectively activate autophagy to entrapthreatening molecules into autophagosomes and clear them via autophagic degradation. For example, microglial TLR4-induced activation of nuclear factor kB (NF-KB) upregulatesp62/SOSTM1 signaling, which degrades misfolded a-syn proteins via autophagy and protects against midbrain dopaminergic neuronal loss (49]. Furthermore, aging-mediated alteration in microglial functions disrupts microglial regulation of autophagy and promotes neuronal loss.

Aging has been recognized as a major risk factor for many neurodegenerative disir. orders. Advanced aging includes several hallmarks indicating risks of developing neu. degenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), and frontotemporal lobar (FID) disease. Furthermore, microglial cells change with aging which is one of the major risk factors for age-related development of neurodegenerationAlthough neurodegenerative diseases are multifactorial conditions, and their complexity is not yet well understood, there has been scientific agreement on the degenerative diseases and age-related changes they can cause in the neural microenvironment.

Aging produces the common feature of high heterogeneity in microglia, which is also a common phenotype of different neurodegenerative diseases 39]. Moreover, the pattern of microglial gene expression changes with aging and neurodegenerative conditions (50The major phenotypic changes in aging microglia are increased soma volume, a retraction in processes, and a loss in uniform tissue distribution (51]. Furthermore, microglial activation slows with age, reducing sensing activity and impairing synaptic contact (6)This process of aging microglial activation is distinct from classical activation and is referred to as microglial dystrophy; the anomalous activation is more likely to be sensitive. cent rather than a classical phenotype (52,53]. Moreover, a new phenotype of microglia has been defined-dark microglia-characterized by condensed electron-dense cytoplasm and nucleoplasm, nuclear chromatin remodeling, and high levels of synaptic stripping activity and oxidative stress [54,55]. Interestingly, these phenomena have not only been observed in microglial populations associated with chronic stress or diseases such as AD but also in the microglia in normally aging brains [54]. Although knowledge of these molecular structural changes is still in its infancy, it has already been established that aging microglia are highly granular and presents an uncharacteristic dark appearance in immunohistological preparations. Another phenotypic change in aged microglia is defective lysosomal digestion. This defect largely privileges the accumulation of indigestible material composed of lipofuscin and other autofluorescent pigments [56,57]. Therefore, the use of immunofluorescence or flow cytometry has become familiar among researchers to distinguish between normal and aged microglia. Accumulation of such autofluorescent pigments and lipofuscin is believed to be a by-product of impaired disposal mechanisms and purported to have a direct relation to several neurodegenerative diseases, including AD [58,59].

Microglial changes with age do not follow one specific process but, rather, change throughout one’s life; after reaching a certain age, threshold impacts will appear. Transcriptome analysis of the frontal cortex region of post-mortem healthy brains across a wide age range (from young teenagers to people over 80 years old) showed that microglial gene markers assemble into a transcriptional module in a gene co-expression network [60], and this expression pattern negatively correlates with age. Another study revealed that genes that encode microglia surface receptors for neuronal and/or microglial crosstalk are particularly affected. Several brain-expressed transcription factors, including RUNX1, IRF8, PU.1, and TAL1, are the master regulators of age-dependent microglial modulation [39]. This raises the question of how important it is to identify age-dependent genetic modulation in adulthood to understand neurodegenerative disease pathology. Identification at the beginning of genetic changes in middle or late-middle age might correlate with several chronic neurodegeneration initiations and thus may help stall disease progression.

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The Effectiveness of Cistanche Extract in improving memory

Cistanche is a traditional Chinese medicinal herb that has been used for centuries to treat various health conditions, including memory problems. Researchers have become increasingly interested in the potential of Cistanche extract as a natural remedy for cognitive decline and memory loss, as there is growing evidence to suggest that the herb may offer several benefits for brain health.

One of the key components of Cistanche extract is echinacoside, which has been shown to have neuroprotective effects, meaning it helps protect brain cells from damage caused by oxidative stress and inflammation. Additionally, echinacoside can increase the production of nerve growth factors, which are essential for the growth and survival of neurons in the brain.

Several studies have investigated the effectiveness of Cistanche extract in improving memory function, with promising results. One study published in the Journal of Ethnopharmacology found that treatment with Cistanche extract improved memory performance in rats with cognitive impairment induced by scopolamine. The researchers concluded that Cistanche extract may be a potential therapeutic agent for the prevention and treatment of memory deficits.

Another study published in the journal Nutrients examined the effects of Cistanche extract on cognitive function in healthy young adults. Participants who took Cistanche extract experienced improvements in attention, working memory, and reaction time compared to those who took a placebo. The researchers suggested that Cistanche extract may be a useful supplement for individuals seeking to improve cognitive function.

Despite these promising findings, more research is needed to fully understand the potential benefits of Cistanche extract for memory improvement. It is also important to note that while Cistanche extract appears to be safe, it may have interactions with certain medications and should not be taken without first consulting a healthcare professional.

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In summary, while further studies are needed, current research suggests that Cistanche extract may have the potential to improve memory function. Its neuroprotective properties, coupled with its ability to promote nerve growth factors, make it a promising natural remedy for cognitive decline and memory loss. However, individuals interested in taking Cistanche extract should first consult their healthcare provider to ensure safe and appropriate use.

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