Microglia in the aging brain: relevance to neurodegeneration

“By using in vivo two-photon imaging techniques, Nimmerjahn et al[37].”

“Extrinsic factors might include neurotransmitter, oxidative stress, neuroendocrine factors[10,68], hormones, and pathological factors such as abnormal protein aggregation [52] that exists in the microenvironment where microglia live.”

“When triggered by appropriate stimulation, microglia rapidly transformed from a resting state to an activated state with deramified shape and enhanced antigen presentation, which has been graded to a series of stages[18].”

“Microglia are distributed ubiquitously throughout the brain and function as resident macrophages and antigen-presenting cells in the CNS[35,36].”

“These studies indicate that microglia are capable of being both neurotrophic and neurotoxic, depending on the specific stimulus, the severity of injury, and the environment [31-34].”

“These genes include Abbinding scavenger receptors A (SRA), CD36, receptor for advanced glycosylation end products (RAGE), Abdegrading enzymes (insulysin, neprilysin) and MMP9 [74].”

“Insulin-like signaling pathway has been shown to regulate life span in worms, flies, and mice[ 72 ].”

“Microglia activation is normally controlled under physiological conditions of the CNS through neuron-glia contact, CD200R-CD200 pathway[19], neuronal electrical activity[20], and/or some soluble neurotransmitters [21].”

“”[50] Characteristics of “dystrophic” microglia that were observed in the aged brain include deramification (loss of finely branched cytoplasmic processes), cytoplasmic beading/spheroid formation, shortened and twisted cytoplasmic processes, and instances of partial or complete cytoplasmic fragmentation[50].”

“The considerable contribution of microglia activation to the pathogenesis of PD has long been proposed [45,46,75].”

“Isolated microglia from aged brains exhibit decreased process complexity, altered granularity, and increased basal cytokines as compared to those from the young brain, suggesting an elevated inflammatory state in the aged microglia[56].”

“It is still uncertain what triggers the microglial activation in the healthy aged brain; whether it is caused by degenerating neurons or by abnormal protein aggregation found in clinically normal elders is still unknown[22].”

“reported a reduced Toll-like receptor (TLR) expression in macrophages with advanced age[11], while Boehmer et al [12].”

“Microglia are distributed ubiquitously throughout the brain and function as resident macrophages and antigen-presenting cells in the CNS[35,36].”

“Most of the debate has arisen from in vitro studies [ 27-30 ], which usually give ambiguous effects of microglia on cultured neurons.”

“However, if the microglia activation in the brain oversteps the threshold of tolerability, it might contribute to pathology rather than have a sentinel or defensive role [ 38 ].”

“found upregulation of genes related to purine biosynthesis, heat-shock proteins, antioxidants, and innate immune responses in old flies and in oxygen-stressed flies, suggesting the specific gene expression profile during aging [71].”

“Once activated, they are committed to various phenotypes[38,40,69].”

“Microglia have been demonstrated to protect neurons against ischemia either by synthesis of tumor necrosis factor[42] or by engulfment of harmful invading neutrophil granulocytes[43].”

“In this slowly progressive procedure, activated microglia has been demonstrated to play important detrimental roles [45-47].”

“In rodents, the cytokine production (interleukin 1 (IL-1), tumor necrosis factor (TNF-a)) [6-9] as well as oxidative radicals and iNOS expression [9] were reported to decline in macrophages with aging.”

“Microglia activation is normally controlled under physiological conditions of the CNS through neuron-glia contact, CD200R-CD200 pathway[19], neuronal electrical activity[20], and/or some soluble neurotransmitters [21].”

“who reported that microglial cells exhibit significant telomere shortening and reduction of telomerase activity during normal aging in rats[54].”

“et al. reported a reduced Toll-like receptor (TLR) expression in macrophages with advanced age[11], while Boehmer et al [ 12 ].”

“The considerable contribution of microglia activation to the pathogenesis of PD has long been proposed [45,46,75].”

“Microglia have been demonstrated to protect neurons against ischemia either by synthesis of tumor necrosis factor[42] or by engulfment of harmful invading neutrophil granulocytes[43].”

“During normal aging of the monkey brain, microglial expression of MHC class II increases with age[23], and the phagocytic activity of microglia increases age-dependently, leading to electron dense inclusions that have the appearance of myelin in microglia[24].”

“Activated microglia can also clear glutamate without evoking inflammatory mediators after traumatic injury and thus reduce neurotoxicity[40].”

“Additionally, increased pro-inflammatory cytokines and decreased anti-inflammatory cytokines have been demonstrated from lipopolysaccharide (LPS)-activated microglia explanted from aged mice[26], suggesting the abnormal immune state of microglia in the aged brain.”

“During normal aging of the monkey brain, microglial expression of MHC class II increases with age[23], and the phagocytic activity of microglia increases age-dependently, leading to electron dense inclusions that have the appearance of myelin in microglia[24].”

“Microglia activation in the aged brain It has been proposed that aberrant inflammatory responses play a role in the etiology of several neurodegenerative diseases, such as Parkinson’s disease (PD) or Alzheimer’s disease (AD)[13,14], in which aging is the most important risk factor.”

“Many studies have demonstrated coexisting neuro-inflammation and neurodegeneration[15,16].”

“The distinct pattern of microglia response to injury in the aged brain has also been recorded in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity[59], the model of controlled cortical impact (CCI)[60], cortical stab injury [61], and transient retinal ischemia[62].”

“Immunohistochemical studies by using activated microglia marker OX-6 staining also found microglial activation with age-related changes[25].”

“Walker et al[70] demonstrated that when compared with those from non-demented brains, large alterations in gene transcription were found in microglia derived from postmortem AD brain, including upregulation of many proinflammatory cytokines and chemokines such as IL1b, IL-8, and matrix metalloproteinases (MMP).”

“The protective roles of activated microglia have also been extensively discussed in multiple sclerosis[44].”

“For example, amyloid has been shown to accelerate microglia senescence[52].”

“However, the senescenced microglia are not universal in the aged brain since scattered dystrophic microglia are usually found alongside normal ramified microglial cells, suggesting that only a subset of microglia become dystrophic, and not all of them are of the same age and functional state[55].”

“The distinct pattern of microglia response to injury in the aged brain has also been recorded in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity[ 59 ], the model of controlled cortical impact (CCI)[60], cortical stab injury [61], and transient retinal ischemia[62].”

“Although the compromise of adaptive immunity mediated by T and B lymphocytes has gained a significant amount of attention [3-5], the innate system also experiences significant changes with advanced age[2].”

“Even though Streit et al[64] gave a suggestion in the difference between the two, describing that “hypertrophy and retraction and thickening of process” occurs in activation while “deramification, shortening and twisting of processes, cytoplasmic fragmentation” are features of aging, so far no definite biomarker or mo…”

“Ramified activated microglia are mainly associated with periventricular region, whereas innate, amoeboid phagocytic phenotype of microglia is seen within the deep subcortical region[67].”

“Are the age-related alterations in microglia function and morphology resulting from intrinsic or extrinsic factors? Does microglia over-activation and malfunction in the aged brain come from their failure to respond correctly to their microenvironment, or from an overloaded toxic microenvironment? It has been demonstr…”

“Microglia activation is normally controlled under physiological conditions of the CNS through neuron-glia contact, CD200R-CD200 pathway[19], neuronal electrical activity[20], and/or some soluble neurotransmitters [21].”

“The CNS is relatively immune-privileged, in which the activity of adaptive immunity mediated by lymphocytes is scarce[17].”

“The distinct pattern of microglia response to injury in the aged brain has also been recorded in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity[59], the model of controlled cortical impact (CCI)[60], cortical stab injury [ 61 ], and transient retinal ischemia[62].”

“Such dystrophic microglia were prevalent and extensively distributed in the brain of older human subjects[50,51], whereas normal ramified microglial morphology with only rare instances of dystrophic microglia are seen in the young brain[49] These observations provide initial evidence of the age-associated changes in m…”

“In the mouse hippocampus, the basal expression of 128 genes changes with aging[73].”

“Most of the debate has arisen from in vitro studies [27-30], which usually give ambiguous effects of microglia on cultured neurons.”

“Thus, increased microglia activation[78] and/or senescenced microglia in the aged brain has put the dopaminergic neurons in a more dangerous environment than that of the young brain.”

“Although the compromise of adaptive immunity mediated by T and B lymphocytes has gained a significant amount of attention [ 3-5 ], the innate system also experiences significant changes with advanced age[2].”

“In a study of intracerebral hemorrhage in young and aged rats, it was observed that microglia activation was significantly higher in young rats than in aged ones when examined three days after hemorrhage [ 58 ].”

“Many studies have demonstrated coexisting neuro-inflammation and neurodegeneration[15,16].”

“Microglia senescence renders microglia to function abnormally, to fail to respond correctly to stimuli[48,49] and, eventually, to promote neurodegeneration.”

“Previous studies have shown that telomere shortening, which is a sign of cell senescence, occurs in rat microglia overtime in vitro [52], as well as in vivo in rat cerebellum and cerebral cortex with age[53].”

“Most of the debate has arisen from in vitro studies [ 27-30 ], which usually give ambiguous effects of microglia on cultured neurons.”

“However, both compromised amyloid-clearing ability of microglia[80] and the damage of microglia by amyloid[81] have been reported in AD brain.”

“Although the compromise of adaptive immunity mediated by T and B lymphocytes has gained a significant amount of attention [3-5], the innate system also experiences significant changes with advanced age[2].”

“In axotomy of the optic nerve of amphibians, a rapid microglia response is exhibited with efficient clearance of myelin debris (which contains inhibiting molecules of axon growth) and finally successful axonal regeneration[39].”

“Microglia senescence renders microglia to function abnormally, to fail to respond correctly to stimuli[48,49] and, eventually, to promote neurodegeneration.”

“In rodents, the cytokine production (interleukin 1 (IL-1), tumor necrosis factor (TNF-a)) [6-9] as well as oxidative radicals and iNOS expression [9] were reported to decline in macrophages with aging.”

“Are the age-related alterations in microglia function and morphology resulting from intrinsic or extrinsic factors? Does microglia over-activation and malfunction in the aged brain come from their failure to respond correctly to their microenvironment, or from an overloaded toxic microenvironment? It has been demonstr…”

“of neurons[79].”

“Aging is the strongest risk factor for PD, which is true not only in the epidemiological studies, but also in the models of PD. A low systemic dose of rotenone had no effect on young rats, but led to a2 0- 30% reduction of dopaminergic neurons in the substantia nigra of older rats[ 76 ].”

“The distinct pattern of microglia response to injury in the aged brain has also been recorded in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity[59], the model of controlled cortical impact (CCI)[60], cortical stab injury [61], and transient retinal ischemia[62].”

“Most of the debate has arisen from in vitro studies [27-30], which usually give ambiguous effects of microglia on cultured neurons.”

“In rodents, the cytokine production (interleukin 1 (IL-1), tumor necrosis factor (TNF-a)) [6-9] as well as oxidative radicals and iNOS expression [9] were reported to decline in macrophages with aging.”

“These studies indicate that microglia are capable of being both neurotrophic and neurotoxic, depending on the specific stimulus, the severity of injury, and the environment [31-34].”

“By not responding to normal regulatory feedback mechanisms and/or having an impairment in their ability to clear Ab, microglia cells lose their ability to handle potentially toxic compounds and become cytotoxic due to their persistent activation[77].”

“However, both compromised amyloid-clearing ability of microglia[80] and the damage of microglia by amyloid[81] have been reported in AD brain.”

“observed. In an intracerebral hemorrhage model of senescence-accelerated prone mice (SAMP8) and senescence-accelerated resistant mice (SAMR1), brain neutrophils and reactive astrocytes do not differ in number or distribution between SAMP8 and SAMR1 mice, but activated amoeboid microglia are distributed more abundantly…”

“Hurley SD, Coleman PD: Facial nerve axotomy in aged and young adult rats: analysis of the glial response.”

“Microglia activation in the aged brain It has been proposed that aberrant inflammatory responses play a role in the etiology of several neurodegenerative diseases, such as Parkinson’s disease (PD) or Alzheimer’s disease (AD)[13,14], in which aging is the most important risk factor.”

“These studies indicate that microglia are capable of being both neurotrophic and neurotoxic, depending on the specific stimulus, the severity of injury, and the environment [31-34].”

“These studies indicate that microglia are capable of being both neurotrophic and neurotoxic, depending on the specific stimulus, the severity of injury, and the environment [31-34].”

“Extrinsic factors might include neurotransmitter, oxidative stress, neuroendocrine factors[10,68], hormones, and pathological factors such as abnormal protein aggregation [52] that exists in the microenvironment where microglia live.”

“These parameters indicate that as humans and rodents age microglia take on a phenotype consistent with a pro-inflammatory response, even in the absence of overt pathological stimuli (Luo et al. 2010; Choi & Won, 2011; Wong, 2013; Sierra et al. 2014; Ojo et al. 2015; Barrientos et al. 2015a).”

“…aging changes in microglia have been hypothesized to drive the pathogenic progression through a diminution of neuroprotective functions, direct increases in neurotoxicity, and dysregulated responses to signals and perturbations (Flanary et al., 2007; Streit et al., 2008; Luo et al., 2010).”

“…hypothesized that changes in the aging microglia drive pathogenic progression of diseases or injury through a diminution of neuroprotective functions, increase in neurotoxicity, and dysregulation of responses to signals and perturbations (Flanary et al., 2007; Lopes et al., 2008; Luo et al., 2010).”

“…Farina et al., 2007; Inman and Horner, 2007; Johnson et al., 2007; Hammam et al., 2008; Tezel, 2009; Ebneter et al., 2010; Graeber and Streit, 2010; Luo et al., 2010; Bosco et al., 2011, 2012; Kettenmann et al., 2011; London et al., 2011; Bosco et al., 2012; Gallego et al., 2012; Varnum and…”

“Another feature of brain inflammaging is microglial activation, which is characterized by increased soma size and is observed during aging and neurodegenerative diseases (Luo et al., 2010; Norden & Godbout, 2013).”

“However, insufficient microglial clearance function, as observed in many neurodegenerative diseases, may pave the way for interneuronal propagation of pathogenic exosomal a-synuclein species (Luo et al., 2010).”

“These neuronal alterations, however, may be secondary to the larger age-related changes in glial cells that have been associated with decreased neuroprotective function and increased neurotoxicity (Flanary et al., 2007; Luo et al., 2010; Lynch, 2010; Streit et al., 2008; von Bernhardi et al., 2010).”

“An alternative explanation is that chronically progressing large volumes of ischemic neuronal and glial injury, and the ensuing inflammatory response, promotes microglial senescence (the dysfunction and dystrophy of microglia with advancing age).(31) It is of interest that, irrespective of myeloperoxidase, we observed…”

“More specifically, upregulation of the inflammatory inducers/sensors such as TLRs, transducers Trif and MyD88, and amplifiers such as IL-1 and IL-6 has been reported (C. Luo et al., 2010; Tezel, Yang, Luo, Cai, & Powell, 2012).”

“(From Luo et al.,2010 with permission). in the young brain to neurotoxic in the aged brain upon activation [147].”

“, 2004) and microglia (Wyss-Coray et al., 2001; El Khoury and Luster, 2008; Luo et al., 2010) can degrade A to eliminate it from the brain.”

“Microglia undergo a mild and chronic reactive response in aged brains 86,87 , whereas LPS-induced reactivity is firm and transient 77,88 .”

“…has also been recognized, particularly in pathologies associated with the chronic inflammatory phenotype seen in the elderly, such as cardiovascular disease, neurodegeneration, and declined immune function (Kuilman et al., 2008; Freund et al., 2010; Luo et al., 2010; Gorospe & Abdelmohsen, 2011).”

“Likewise, in the human healthy aged brain increased microglia activation with an increased susceptibility to pro-inflammatory activation has been reported [10, 40, 63].”

“As expected for aging brain tissue (Luo et al., 2010), the expression of proinflammatory genes involved in antigen presentation, interferon-, cytokine-, and chemokine signaling, and phagocytosis were enhanced in aged microglia.”

“Nevertheless, the hypothesis of microglia senescence during aging and related neurodegenerative diseases emerged as a key determinant (Luo et al., 2010).”

“Even in the absence of trauma or pathology, microglia priming may occur as a consequence of normal aging (Luo et al., 2010).”

“160,161 Furthermore, A β can function as a DAMP and activate the in fl ammasome via the TLR pathway, leading to the production of in fl ammatory cytokines such as IL-1 β .”

“The observed morphologic changes resemble previously reported microglia phenotypes referred to as “ hypertrophic ” (Ayoub and Salm, 2003; Streit, 2000), “ reactive ” (Gomide et al., 2005), or “ intermediate ” (Karperien et al., 2013).”

“Upon aging microglia show increased immunoreactivity for CD68, a lysosome associated phagocytic receptor, Toll-like-receptors (TLRs), MHC Class II antigen, Matrix remodeling enzyme MMP-12, Cd11b, and Cd11c integrins and cytokines (Luo et al., 2010).”

“Microglial and astrocytes cell uncontrolled activation, increased in an age-dependent manner, leads to excessive inflammation [78].”

“Heat-shock elements can be found in the promoter region of CXC chemokine genes as well, although a heat shock has gene-specific enhancing or repressing effect on the expression of these genes (Maity et al., 2011).”

“contribute to behavioral and cognitive deficits [14], other glia-type cells including astrocytes also display pivotal roles in regulating”

“dysfunctional microglia have been suggested as an initiating factor in AD pathogenesis ( Luo et al. 2010 ).”

“The former interacts with LRP family members on phagocytes (Maiti et al., 2008), whereas the receptor for annexin I remains elusive.”

“Since pro-inflammatory microglia are implicated in several brain diseases [69, 70], future work will have to verify the safety and tolerability of our combination treatment prior to clinical application.”

“Aging also leads to the accumulation of senescent brain immune cells (microglia), a process linked to neurodegenerative pathologies such as Parkinson’s and Alzheimer’s diseases [38].”

“In AD, the microglia play important roles in Aβ clearance and neuroinflammatory response via secretion of pro-inflammatory cytokines [79].”

“Therefore, microglia senescence could play a role in the development of some neurodegenerative conditions [161, 166].”

“However, an uncontrolled microglia response may be dangerous to the survival of injured neurons or can even damage healthy neurons afflicted by excessive inflammation [18].”

“For instance, senescent cells accumulate in Parkinson’s and Alzheimer’s diseases, and impair vascularization in diabetes.(26,27) Senescence of skeletal muscle cell and satellite cells has also been linked to the age-related muscle disorder sarcopenia.”

“For example, accumulation of senescent microglia with aging is linked to neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases (Luo et al., 2010), while the impaired vascularization in diabetes is linked to the enhanced senescence of endothelial progenitor cells (Rosso et al.,…”

“Aging Does Not Affect the Phagocytosis of Exosomes by Microglia Age-associated microglial senescence in the brain leads to abnormal function and may eventually promote neurodegeneration (Luo et al., 2010).”

“Parkinson’s disease (PD) and Alzheimer’s disease (AD) are ge-dependent neurodegenerative disorders [94].”

“Over-activation of microglia may cause alterations in immunophenotypic expression and inflammatory profile (promoting microglia senescence), and that condition may switch microglial function from neuroprotective to neurotoxic effects [52].”

“While microglia cells have a neuroprotective role in the young brain, multiple studies have shown that they gradually transition to a chronically activated and neurotoxic state in older adults (Luo et al., 2010), irrespective of their cognitive status (Gefen, 2019; Niraula et al., 2017).”

“…can act as antigen-presenting cells, and can transform into phagocytes (Karlstetter et al., 2015; Karlstetter et al., 2015; Kettenmann et al., 2011; Kettenmann et al., 2011; Luo et al., 2010; Luo et al., 2010; Ramírez et al., 2015; Ransohoff and Perry, 2009; Kezic et al., 2013; Wang et al., 2017).”

“Aβ deposits also trigger microglia-mediated neuroinflammation, postulated to contribute to the pathogenesis and progression of AD (Giulian et al., 1995; Minghetti, 2005; Floden et al., 2005; Luo et al., 2010).”

“and invasion can be a determinant of altered function in CNS injury and inflammation.(71,72) The soluble but reactive Tau oligomers can readily diffuse through brain parenchyma and attracts microglial chemotaxis.”

“However, chronically activated microglia may initiate inflammatory processes that lead to neuronal dysfunction and damage.(15,16) Thus, tight regulation of”

“Recent papers have underlined the senescence of microglia in AD, with loss of their neuroprotective properties, preceding the onset of tau pathology [90], suggesting that breakdown of the brain’s immune system may be an important factor in the development of neurodegeneration [91].”

“Microglia senescence appears to underlie the switching of microglia from neuroprotective in the young brain to neurotoxic in the aged brain [85].”

“These cytokines activate neurodegenerative pathways [21].”

“…may have a “destroyer” role; actively facilitating the degenerative processes of Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis and other neurodegenerative disorders (Barger and Harmon, 1997, Streit, 2004, Ponomarev et al., 2006, Block et al., 2007, Luo et al., 2010).”

“The changes observed in the AD brain samples, and perhaps in the aging brains in general [40], could be related to disproportional loss of neurons compared with neuroglia observed in AD [41].”

“Activated microglia have been reported in numerous neurodegenerative diseases where aging impairs microglial functions due to increased sensitivity towards pro-inflammatory signals (Luo et al. 2010; von Bernhardi et al. 2010).”

“Microglial senescence with increased susceptibility to activation has been implicated in age-related neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease (Lee and Landreth, 2010; Luo et al., 2010; von Bernhardi et al., 2010).”

“…channels is the hallmark of overactivated microglia (Kettenmann et al., 1993; Noren-berg et al., 1994; Nguyen et al., 2017; Di Lucente et al., 2018; Sarkar et al., 2020), while uncontrolled microglial activities aggravate the neurodegeneration in PD (Luo et al., 2010; Badanjak et al., 2021).”

“For example, mitochondrial dysfunction, oxidative stress, inflammatory response and proteotoxicity are common themes in AD and brain aging [2,3,4,5].”

“These data together imply that benfotiamine exhibits significant antioxidative activity in BV-2 cells.”

“The effect of aging on microglial activity is extremely important, as it is known that aging has an inverse relationship with the activity of the microglia, and aging causes changes in gene expressions, dystrophic microglia, and abnormal cytoplasmic formation, decreasing the microglia’s elasticity and lowering the act…”

“It is speculated that any changes in glial activation during aging are key components that influence the pathogenesis of neurodegeneration [36].”