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].”

“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].”

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

“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 ].”

“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].”

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

“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].”

“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).”

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

“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].”

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

“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 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…”

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

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

“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].”

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

“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].”

“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).”