- Email: [email protected]
Human CNS immune senescence and neurodegeneration
Available online at www.sciencedirect.com
ScienceDirect Human CNS immune senescence and neurodegeneration Wolfgang J Streit and Qing-Shan Xue Microglial cells comprising the brain’s immune system are essential for ensuring neuroprotection in the normal and pathological CNS. On the basis of histopathological observations in human brain, we believe that the ability of microglia to provide neuroprotection deteriorates as our brains get older and that such CNS immune senescence is a major factor contributing to the development of aging-related neurodegenerative diseases, notably Alzheimer’s disease. The idea is consistent with the fact that immune senescence occurs naturally in the periphery, rendering the elderly people more susceptible to infections and cancers. There is an analogous situation in the brain, except that here the main impact comes down to diminished neuroprotection and resultant neurodegeneration. Addresses Department of Neuroscience, University of Florida College of Medicine and McKnight Brain Institute, Gainesville, FL 32610, USA Corresponding author: Streit, Wolfgang J ([email protected], [email protected])
brain and spinal cord. We view microglia as ‘hybrids’ between glial cells and leukocytes since they combine typical neural morphology with immunological functions. Their main function overall is to protect and support neurons, both as leukocytes and as glial cells, meaning they are capable of eliminating potentially harmful, foreign invaders while also providing trophic and tropic support for neurons at all times, especially when neuronal function is compromised and microglia become activated. The maintenance, repair and restoration of neuronal function through trophic glial–neuronal interactions appear to be the more important day-to-day functions of microglia than eliminating pathogens, as the brain already has very effective barriers guarding against infection, that is skull, meninges, cerebrospinal fluid, and BBB, and healthy adults rarely develop brain infections. Thus, while studies of peripheral immune function are mostly concerned with mechanisms underlying neutralization of infectious agents, this may be of lesser importance when it comes to assessing microglial cell functions.
Current Opinion in Immunology 2014, 29:93–96
Degenerative or inflammatory?
This review comes from a themed issue on Immune senescence
Over the past couple of decades, the view that chronic inflammation contributes to neuronal degeneration in major aging-related neurodegenerative disease states, that is, Alzheimer’s and Parkinson’s disease (AD and PD), has taken a strong foothold in neuroscience. Accordingly, the term neuroinflammation has gained pervasive popularity and has even spread to encompass conditions where there are no apparent neurodegenerative changes or neuronal loss, such as neuropsychiatric disorders [1,2]. Prior to 1995, neuroinflammation was not part of the neuroscience vocabulary [3], even though a variety of CNS lesions marked by inflammation had long been known to exist (e.g. infections, tumors, trauma, and demyelination). So, how did neuroinflammation become implicated in neurodegenerative diseases, conditions that had always been characterized as degenerative and never had an inflammatory pathogenesis associated with them? The answer has to do in part not only with true, objective scientific advances and discoveries, but also with some rather subjective perceptions and precipitate interpretations. Unfortunately, the latter resulted in producing a neuroinflammation neologism that is marked by lack of a clear definition and an implicitly exaggerated significance.
Edited by Tamas Fu¨lo¨p and Ruth Montgomery
http://dx.doi.org/10.1016/j.coi.2014.05.005 0952-7915/# 2014 Elsevier Ltd. All rights reserved.
Introduction Immune surveillance in the central nervous system (CNS) is different from immune surveillance in the periphery. Leukocytes (lymphocytes, monocytes, neutrophils, and so on), which can freely infiltrate peripheral organs of the body, do not have unrestricted access to the CNS parenchyma under normal conditions. This restriction occurs primarily because of the tight junctions between brain endothelial cells which in essence constitute the blood–brain barrier (BBB). Adaptive immunity therefore appears to play a minor role in the normal CNS where instead the innate immune system dominates. The latter comprises microglia, cells of the monocyte/macrophage lineage that exhibit the characteristic process-bearing morphology of most other brain cells and distribute ubiquitously in a network-like fashion throughout the www.sciencedirect.com
Inflammation is defined as the reaction of living tissue to all forms of injury irrespective of whether it occurs in the CNS or elsewhere. Cellular responses to injury are Current Opinion in Immunology 2014, 29:93–96
94 Immune senescence
performed typically by blood-borne leukocytes, and an acute inflammatory infiltrate can be distinguished from a chronic one by the types of leukocytes present [4]. However, in the CNS a reaction to neuronal damage can occur without direct participation of blood-borne cells and may involve solely the activation of endogenous glial cells (microglia and astrocytes) as long as the lesion does not produce damage to the blood–brain barrier (BBB). While astroglial and microglial activation had long been known to occur in a variety of injury and disease scenarios, detecting microglia was historically difficult for lack of specific reagents and reliable histochemical methods. The availability of antibodies specific for microglia in the 1980s marked a major scientific advance which rejuvenated the microglial field and produced an impressive increase in the literature describing microglial reactions to various kinds of experimental CNS injuries. Microgliaspecific antibodies were also used to study microglia in diseased human tissues and resulted in the identification of reactive microglia in AD and most other major neurodegenerative disease states [5–7]. At about the same time, another scientific advance represented by the development of methods for maintaining microglia in vitro was taking place (reviewed in [8]), and these cell culture studies produced the notion that activated microglia were dangerous, neurotoxin-producing immune effector cells intent on killing neurons [9,10]. The extrapolation of this in vitro notion to the human brain where activated microglia had been associated with neurodegenerative diseases was a major factor in developing the hypothesis that a chronic and detrimental inflammatory response mediated by activated microglia cells is what causes neurodegeneration in AD [11]. However, there are significant caveats associated with the neuroinflammation idea in terms of its conception and meaning, as well as its applicability for finding new treatments. First, the extrapolation of microglial functions described in vitro to the diseased human brain is unjustifiable. Cultured microglia, typically derived from very young rodent brains, are different cells than their counterparts found in aged human brains [12], not only in terms of chronological age and species but they are also maintained in isolation in an artificial, non-physiological environment. Their activation in vitro with LPS or other potent immunostimulatory agents does not simulate the type of sterile pathophysiological activation that occurs in vivo [13], and microglial production of neurotoxins in vitro is not recapitulated in vivo where instead activated microglia work to restore homeostasis after injury has occurred. Moreover, in AD, the timing of onset of allegedly detrimental microglial activation is unknown and its chronic presence is merely assumed. Its detrimental character is conjectured from said in vitro studies using extreme immune stimulation with agents that essentially mimic infectious disease, and its causative role in the development of neurofibrillary degeneration is speculative and Current Opinion in Immunology 2014, 29:93–96
unsubstantiated by observations in human brain or in AD animal models. We have shown recently that the presence of severe neuroinflammatory changes in human brain, including widespread microglial activation and leukocytic infiltration, does not exacerbate existing neurofibrillary degeneration, which occurs to the same extent in inflamed human brains as it does in brains without neuroinflammatory changes [14]. Second, the in situ criteria that have been used to claim the presence of microglial activation in AD brain, that is, increased immunoreactivity for histocompatibility antigens (HLA-DR), clustering of microglia at sites of amyloid deposition, and interleukin-1 expression, are problematic and overshadowed by concerns about pro-inflammatory comorbidities, such as sepsis [14]. They clearly do not constitute sufficient evidence to claim that chronic inflammation directly causes neurofibrillary degeneration. Third, a chronic and often detrimental inflammatory infiltrate consists of macrophages, lymphocytes, and plasma cells and such infiltrates do not exist in the AD brain, and there is certainly no evidence of brain swelling at any point during disease development as might be reasonably expected to occur during longstanding chronic inflammation. There is also no evidence of any persistent injurious trigger that could produce a chronic inflammatory response. Moreover, tissue damage caused by severe inflammation presents as necrosis and not as neurofibrillary degeneration [14]. Fourth, the use of non-steroidal anti-inflammatory drugs in clinical trials has yielded no evidence to suggest that these drugs are useful for halting the development or slowing the progression of neurofibrillary degeneration [15–17]. Fifth, tau-positive, degenerating structures in the AD brain (neurofibrillary tangles, pretangles, neuropil threads and neuritic plaques) do not show an association with activated microglia as would be expected if the neuroinflammation theory was valid. Instead, tau-positive structures are seen in association with dystrophic microglia [18]. Thus overall there is very little convincing evidence in favor of neuroinflammation being the immediate trigger for the development of AD-type neurodegeneration.
Structural changes in microglia are indicative of CNS immune senescence The idea that microglia are subject to senescent deterioration stems from histological observations in the non-diseased human brain, showing that with aging an increasing proportion of microglial cells display abnormal morphological features that are construed to reflect cell senescence [17]. Collectively, the rather diverse structural changes affecting the microglial cytoplasm are designated as microglial dystrophy as they are distinct from morphological changes that characterize activated microglia, that is, cytoplasmic hypertrophy. Work in the diseased human brain has shown that dystrophic microglia are particularly abundant in AD brain where they tend to be most prevalent in regions of the temporal lobe www.sciencedirect.com
Human CNS immune senescence Streit and Xue 95
undergoing neurofibrillary degeneration [18]. This observation of close spatial association between dystrophic microglia and tau-positive, degenerating neuronal structures is eye-opening in more than one way: it shows directly that neurofibrillary degeneration is not accompanied by microglial activation indicative of an inflammatory response, and by documenting coexistence of neurodegeneration with dystrophic microglia it supports an alternative hypothesis, namely, that neurofibrillary degeneration may be connected to microglial degeneration. Since our earlier work studying microglia in experimental animal models of CNS injury has led us to conclude that activated microglia are beneficial and of critical importance for facilitating neuronal repair and protection [19], we reason that co-localization of dystrophic microglia and neurofibrillary degeneration may reflect causally linked events. We therefore postulate that deterioration of microglial neuroprotective functions leads to neurodegeneration (Figure 1) [20]. Senescent microglial morphology suggests the presence of functional impairments, yet much remains to be learned about the specific nature of deficits that may be associated with dystrophic microglia during the various stages of their degenerative cascade. Microglial degeneration in human brain is likely a gradually progressive process that occurs slowly over time, and cells can be observed to show varying degrees of structural deterioration ranging from minor blebbing of their plasma membranes to spheroid formation and beading of processes to complete fragmentation of their entire cytoplasm into Figure 1 Oxidative Stress
Aging
Stroke
Amyloid
Genetics
Inflammation Microglial Senescence
Unknown Comorbidities
multiple membrane-bound particles sized in the micrometer range. It seems obvious that such severe fragmentation (cytorrhexis) would render the cells completely non-functional, and the fact that brain regions showing extensive microglial cytorrhexis are typically littered with cellular debris and reveal a striking absence of brain macrophages [4] suggests a marked deficit in microglial phagocytic activity. Furthermore, the fact that degenerating neuronal structures and amyloid deposits are also not being removed via phagocytosis offers additional support that this central function of microglia is compromised [21]. The possibility that a deficit in amyloid-beta phagocytosis is critical for AD development has been discussed independently by several research teams using different experimental approaches [22–25]. Most recently, genetic studies using whole exome sequencing and whole genome sequencing in humans are offering new molecular evidence to support histopathological findings suggestive of microglial immune senescence by showing that rare coding variants in triggering receptor expressed on myeloid cells 2 (TREM2), a known regulator of microglial activation and phagocytosis, confer substantial risk for AD [26,27,28,29]. It is interesting to note that in the context of age-related macular degeneration, genetic association studies of polymorphisms have found that a rare functional haplotype of P2RX4 and P2RX7 was overrepresented in patients with this condition compared to that in controls [30]. Co-expression of both these purinergic receptor variants, which are known to be involved in the regulation of phagocytic activity, was found to almost completely abolish phagocytic activity in HEK cells, and was associated with a significant reduction in phagocytic capacity in human blood monocytes. Thus current understanding of microglial dysfunction, a field still in its infancy, is largely focused on impaired phagocytosis which is a most important role of these cells. However, defective phagocytosis may just be the tip of the iceberg and it is likely that this emerging interest will reveal even broader compromise of microglial cell functions, which will be important for improved understanding of neurodegenerative disease pathogenesis [31].
Acknowledgements We thank the Cooper family of Indialantic, FL, for their support of dementia research.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest
Neurodegeneration Current Opinion in Immunology
Microglial dysfunction hypothesis. Multiple etiological factors contribute to produce microglial senescent degeneration, which is evident pathologically as cytoplasmic fragmentation. Neuronal tau pathology may occur as a result of microglial senescent dysfunction. www.sciencedirect.com
1.
Najjar S, Pearlman DM, Alper K, Najjar A, Devinsky O: Neuroinflammation and psychiatric illness. J Neuroinflammation 2013, 10:43.
2.
Frick LR, Williams K, Pittenger C: Microglial dysregulation in psychiatric disease. Clin Dev Immunol 2013, 2013:608654. Current Opinion in Immunology 2014, 29:93–96
96 Immune senescence
3.
Streit WJ, Mrak RE, Griffin WS: Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation 2004, 1:14.
4.
Streit WJ, Xue QS: Microglial senescence. CNS Neurol Disord Drug Targets 2013, 12:763-767.
5.
McGeer PL, Itagaki S, Tago H, McGeer EG: Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 1987, 79:195-200.
6.
Rogers J, Luber-Narod J, Styren SD, Civin WH: Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease. Neurobiol Aging 1988, 9:339-349.
7.
McGeer PL, Itagaki S, McGeer EG: Expression of the histocompatibility glycoprotein HLA-DR in neurological disease. Acta Neuropathol 1988, 76:550-557.
8.
Streit WJ: Microglial activation and neuroinflammation in Alzheimer’s disease: a critical examination of recent history. Front Aging Neurosci 2010, 2:22.
9.
Giulian D: Reactive glia as rivals in regulating neuronal survival. Glia 1993, 7:102-110.
10. Giulian D, Haverkamp LJ, Li J, Karshin WL, Yu J, Tom D, Li X, Kirkpatrick JB: Senile plaques stimulate microglia to release a neurotoxin found in Alzheimer brain. Neurochem Int 1995, 27:119-137. 11. McGeer PL, McGeer EG: Inflammation, autotoxicity and Alzheimer disease. Neurobiol Aging 2001, 22:799-809. 12. Smith AM, Dragunow M: The human side of microglia. Trends Neurosci 2014. 13. Graeber MB, Li W, Rodriguez ML: Role of microglia in CNS inflammation. FEBS Lett 2011, 585:3798-3805. 14. Streit WJ, Xue QS, Braak H, Del Tredici K: Presence of severe neuroinflammation does not intensify neurofibrillary degeneration in human brain. Glia 2014, 62:96-105. 15. Arvanitakis Z, Grodstein F, Bienias JL, Schneider JA, Wilson RS, Kelly JF, Evans DA, Bennett DA: Relation of NSAIDs to incident AD, change in cognitive function, and AD pathology. Neurology 2008, 70:2219-2225.
19. Streit WJ: Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 2002, 40:133-139. 20. Streit WJ: Microglia and Alzheimer’s disease pathogenesis. J Neurosci Res 2004, 77:1-8. 21. Neumann H, Kotter MR, Franklin RJ: Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 2009, 132:288-295. 22. Fiala M, Lin J, Ringman J, Kermani-Arab V, Tsao G, Patel A, Lossinsky AS, Graves MC, Gustavson A, Sayre J et al.: Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer’s disease patients. J Alzheimers Dis 2005, 7:221-232. 23. Njie EG, Boelen E, Stassen FR, Steinbusch HW, Borchelt DR, Streit WJ: Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol Aging 2012, 33 195 e191–112. 24. Krabbe G, Halle A, Matyash V, Rinnenthal JL, Eom GD, Bernhardt U, Miller KR, Prokop S, Kettenmann H, Heppner FL: Functional impairment of microglia coincides with Betaamyloid deposition in mice with Alzheimer-like pathology. PLoS One 2013, 8:e60921. 25. Hickman SE, Allison EK: El Khoury J: Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci 2008, 28:8354-8360. 26. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ et al.: Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 2013, 368:107-116. 27. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S et al.: TREM2 variants in Alzheimer’s disease. N Engl J Med 2013, 368:117-127. These authors found significantly more variants of TREM2 in AD patients than in control subjects, suggesting that these gene variants are associated with a higher risk of developing AD. The presence of large numbers of TREM2 variants is consistent with the possibility of dysfunctional microglial phagocytosis. 28. Neumann H, Daly MJ: Variant TREM2 as risk factor for Alzheimer’s disease. N Engl J Med 2013, 368:182-184. The significance of identifying TREM2 variants in AD by two independent research groups is discussed
16. Halliday GM, Shepherd CE, McCann H, Reid WG, Grayson DA, Broe GA, Kril JJ: Effect of anti-inflammatory medications on neuropathological findings in Alzheimer disease. Arch Neurol 2000, 57:831-836.
29. Golde TE, Streit WJ, Chakrabarty P: Alzheimer’s disease risk alleles in TREM2 illuminate innate immunity in Alzheimer’s disease. Alzheimers Res Ther 2013, 5:24.
17. Martin BK, Szekely C, Brandt J, Piantadosi S, Breitner JC, Craft S, Evans D, Green R, Mullan M: Cognitive function over time in the Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT): results of a randomized, controlled trial of naproxen and celecoxib. Arch Neurol 2008, 65:896-905.
30. Gu BJ, Baird PN, Vessey KA, Skarratt KK, Fletcher EL, Fuller SJ, Richardson AJ, Guymer RH, Wiley JS: A rare functional haplotype of the P2RX4 and P2RX7 genes leads to loss of innate phagocytosis and confers increased risk of agerelated macular degeneration. FASEB J 2013, 27: 1479-1487.
18. Streit WJ, Braak H, Xue QS, Bechmann I: Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol 2009, 118:475-485.
Current Opinion in Immunology 2014, 29:93–96
31. Fellner L, Jellinger KA, Wenning GK, Stefanova N: Glial dysfunction in the pathogenesis of alpha-synucleinopathies: emerging concepts. Acta Neuropathol 2011, 121:675-693.
www.sciencedirect.com
ScienceDirect Human CNS immune senescence and neurodegeneration Wolfgang J Streit and Qing-Shan Xue Microglial cells comprising the brain’s immune system are essential for ensuring neuroprotection in the normal and pathological CNS. On the basis of histopathological observations in human brain, we believe that the ability of microglia to provide neuroprotection deteriorates as our brains get older and that such CNS immune senescence is a major factor contributing to the development of aging-related neurodegenerative diseases, notably Alzheimer’s disease. The idea is consistent with the fact that immune senescence occurs naturally in the periphery, rendering the elderly people more susceptible to infections and cancers. There is an analogous situation in the brain, except that here the main impact comes down to diminished neuroprotection and resultant neurodegeneration. Addresses Department of Neuroscience, University of Florida College of Medicine and McKnight Brain Institute, Gainesville, FL 32610, USA Corresponding author: Streit, Wolfgang J ([email protected], [email protected])
brain and spinal cord. We view microglia as ‘hybrids’ between glial cells and leukocytes since they combine typical neural morphology with immunological functions. Their main function overall is to protect and support neurons, both as leukocytes and as glial cells, meaning they are capable of eliminating potentially harmful, foreign invaders while also providing trophic and tropic support for neurons at all times, especially when neuronal function is compromised and microglia become activated. The maintenance, repair and restoration of neuronal function through trophic glial–neuronal interactions appear to be the more important day-to-day functions of microglia than eliminating pathogens, as the brain already has very effective barriers guarding against infection, that is skull, meninges, cerebrospinal fluid, and BBB, and healthy adults rarely develop brain infections. Thus, while studies of peripheral immune function are mostly concerned with mechanisms underlying neutralization of infectious agents, this may be of lesser importance when it comes to assessing microglial cell functions.
Current Opinion in Immunology 2014, 29:93–96
Degenerative or inflammatory?
This review comes from a themed issue on Immune senescence
Over the past couple of decades, the view that chronic inflammation contributes to neuronal degeneration in major aging-related neurodegenerative disease states, that is, Alzheimer’s and Parkinson’s disease (AD and PD), has taken a strong foothold in neuroscience. Accordingly, the term neuroinflammation has gained pervasive popularity and has even spread to encompass conditions where there are no apparent neurodegenerative changes or neuronal loss, such as neuropsychiatric disorders [1,2]. Prior to 1995, neuroinflammation was not part of the neuroscience vocabulary [3], even though a variety of CNS lesions marked by inflammation had long been known to exist (e.g. infections, tumors, trauma, and demyelination). So, how did neuroinflammation become implicated in neurodegenerative diseases, conditions that had always been characterized as degenerative and never had an inflammatory pathogenesis associated with them? The answer has to do in part not only with true, objective scientific advances and discoveries, but also with some rather subjective perceptions and precipitate interpretations. Unfortunately, the latter resulted in producing a neuroinflammation neologism that is marked by lack of a clear definition and an implicitly exaggerated significance.
Edited by Tamas Fu¨lo¨p and Ruth Montgomery
http://dx.doi.org/10.1016/j.coi.2014.05.005 0952-7915/# 2014 Elsevier Ltd. All rights reserved.
Introduction Immune surveillance in the central nervous system (CNS) is different from immune surveillance in the periphery. Leukocytes (lymphocytes, monocytes, neutrophils, and so on), which can freely infiltrate peripheral organs of the body, do not have unrestricted access to the CNS parenchyma under normal conditions. This restriction occurs primarily because of the tight junctions between brain endothelial cells which in essence constitute the blood–brain barrier (BBB). Adaptive immunity therefore appears to play a minor role in the normal CNS where instead the innate immune system dominates. The latter comprises microglia, cells of the monocyte/macrophage lineage that exhibit the characteristic process-bearing morphology of most other brain cells and distribute ubiquitously in a network-like fashion throughout the www.sciencedirect.com
Inflammation is defined as the reaction of living tissue to all forms of injury irrespective of whether it occurs in the CNS or elsewhere. Cellular responses to injury are Current Opinion in Immunology 2014, 29:93–96
94 Immune senescence
performed typically by blood-borne leukocytes, and an acute inflammatory infiltrate can be distinguished from a chronic one by the types of leukocytes present [4]. However, in the CNS a reaction to neuronal damage can occur without direct participation of blood-borne cells and may involve solely the activation of endogenous glial cells (microglia and astrocytes) as long as the lesion does not produce damage to the blood–brain barrier (BBB). While astroglial and microglial activation had long been known to occur in a variety of injury and disease scenarios, detecting microglia was historically difficult for lack of specific reagents and reliable histochemical methods. The availability of antibodies specific for microglia in the 1980s marked a major scientific advance which rejuvenated the microglial field and produced an impressive increase in the literature describing microglial reactions to various kinds of experimental CNS injuries. Microgliaspecific antibodies were also used to study microglia in diseased human tissues and resulted in the identification of reactive microglia in AD and most other major neurodegenerative disease states [5–7]. At about the same time, another scientific advance represented by the development of methods for maintaining microglia in vitro was taking place (reviewed in [8]), and these cell culture studies produced the notion that activated microglia were dangerous, neurotoxin-producing immune effector cells intent on killing neurons [9,10]. The extrapolation of this in vitro notion to the human brain where activated microglia had been associated with neurodegenerative diseases was a major factor in developing the hypothesis that a chronic and detrimental inflammatory response mediated by activated microglia cells is what causes neurodegeneration in AD [11]. However, there are significant caveats associated with the neuroinflammation idea in terms of its conception and meaning, as well as its applicability for finding new treatments. First, the extrapolation of microglial functions described in vitro to the diseased human brain is unjustifiable. Cultured microglia, typically derived from very young rodent brains, are different cells than their counterparts found in aged human brains [12], not only in terms of chronological age and species but they are also maintained in isolation in an artificial, non-physiological environment. Their activation in vitro with LPS or other potent immunostimulatory agents does not simulate the type of sterile pathophysiological activation that occurs in vivo [13], and microglial production of neurotoxins in vitro is not recapitulated in vivo where instead activated microglia work to restore homeostasis after injury has occurred. Moreover, in AD, the timing of onset of allegedly detrimental microglial activation is unknown and its chronic presence is merely assumed. Its detrimental character is conjectured from said in vitro studies using extreme immune stimulation with agents that essentially mimic infectious disease, and its causative role in the development of neurofibrillary degeneration is speculative and Current Opinion in Immunology 2014, 29:93–96
unsubstantiated by observations in human brain or in AD animal models. We have shown recently that the presence of severe neuroinflammatory changes in human brain, including widespread microglial activation and leukocytic infiltration, does not exacerbate existing neurofibrillary degeneration, which occurs to the same extent in inflamed human brains as it does in brains without neuroinflammatory changes [14]. Second, the in situ criteria that have been used to claim the presence of microglial activation in AD brain, that is, increased immunoreactivity for histocompatibility antigens (HLA-DR), clustering of microglia at sites of amyloid deposition, and interleukin-1 expression, are problematic and overshadowed by concerns about pro-inflammatory comorbidities, such as sepsis [14]. They clearly do not constitute sufficient evidence to claim that chronic inflammation directly causes neurofibrillary degeneration. Third, a chronic and often detrimental inflammatory infiltrate consists of macrophages, lymphocytes, and plasma cells and such infiltrates do not exist in the AD brain, and there is certainly no evidence of brain swelling at any point during disease development as might be reasonably expected to occur during longstanding chronic inflammation. There is also no evidence of any persistent injurious trigger that could produce a chronic inflammatory response. Moreover, tissue damage caused by severe inflammation presents as necrosis and not as neurofibrillary degeneration [14]. Fourth, the use of non-steroidal anti-inflammatory drugs in clinical trials has yielded no evidence to suggest that these drugs are useful for halting the development or slowing the progression of neurofibrillary degeneration [15–17]. Fifth, tau-positive, degenerating structures in the AD brain (neurofibrillary tangles, pretangles, neuropil threads and neuritic plaques) do not show an association with activated microglia as would be expected if the neuroinflammation theory was valid. Instead, tau-positive structures are seen in association with dystrophic microglia [18]. Thus overall there is very little convincing evidence in favor of neuroinflammation being the immediate trigger for the development of AD-type neurodegeneration.
Structural changes in microglia are indicative of CNS immune senescence The idea that microglia are subject to senescent deterioration stems from histological observations in the non-diseased human brain, showing that with aging an increasing proportion of microglial cells display abnormal morphological features that are construed to reflect cell senescence [17]. Collectively, the rather diverse structural changes affecting the microglial cytoplasm are designated as microglial dystrophy as they are distinct from morphological changes that characterize activated microglia, that is, cytoplasmic hypertrophy. Work in the diseased human brain has shown that dystrophic microglia are particularly abundant in AD brain where they tend to be most prevalent in regions of the temporal lobe www.sciencedirect.com
Human CNS immune senescence Streit and Xue 95
undergoing neurofibrillary degeneration [18]. This observation of close spatial association between dystrophic microglia and tau-positive, degenerating neuronal structures is eye-opening in more than one way: it shows directly that neurofibrillary degeneration is not accompanied by microglial activation indicative of an inflammatory response, and by documenting coexistence of neurodegeneration with dystrophic microglia it supports an alternative hypothesis, namely, that neurofibrillary degeneration may be connected to microglial degeneration. Since our earlier work studying microglia in experimental animal models of CNS injury has led us to conclude that activated microglia are beneficial and of critical importance for facilitating neuronal repair and protection [19], we reason that co-localization of dystrophic microglia and neurofibrillary degeneration may reflect causally linked events. We therefore postulate that deterioration of microglial neuroprotective functions leads to neurodegeneration (Figure 1) [20]. Senescent microglial morphology suggests the presence of functional impairments, yet much remains to be learned about the specific nature of deficits that may be associated with dystrophic microglia during the various stages of their degenerative cascade. Microglial degeneration in human brain is likely a gradually progressive process that occurs slowly over time, and cells can be observed to show varying degrees of structural deterioration ranging from minor blebbing of their plasma membranes to spheroid formation and beading of processes to complete fragmentation of their entire cytoplasm into Figure 1 Oxidative Stress
Aging
Stroke
Amyloid
Genetics
Inflammation Microglial Senescence
Unknown Comorbidities
multiple membrane-bound particles sized in the micrometer range. It seems obvious that such severe fragmentation (cytorrhexis) would render the cells completely non-functional, and the fact that brain regions showing extensive microglial cytorrhexis are typically littered with cellular debris and reveal a striking absence of brain macrophages [4] suggests a marked deficit in microglial phagocytic activity. Furthermore, the fact that degenerating neuronal structures and amyloid deposits are also not being removed via phagocytosis offers additional support that this central function of microglia is compromised [21]. The possibility that a deficit in amyloid-beta phagocytosis is critical for AD development has been discussed independently by several research teams using different experimental approaches [22–25]. Most recently, genetic studies using whole exome sequencing and whole genome sequencing in humans are offering new molecular evidence to support histopathological findings suggestive of microglial immune senescence by showing that rare coding variants in triggering receptor expressed on myeloid cells 2 (TREM2), a known regulator of microglial activation and phagocytosis, confer substantial risk for AD [26,27,28,29]. It is interesting to note that in the context of age-related macular degeneration, genetic association studies of polymorphisms have found that a rare functional haplotype of P2RX4 and P2RX7 was overrepresented in patients with this condition compared to that in controls [30]. Co-expression of both these purinergic receptor variants, which are known to be involved in the regulation of phagocytic activity, was found to almost completely abolish phagocytic activity in HEK cells, and was associated with a significant reduction in phagocytic capacity in human blood monocytes. Thus current understanding of microglial dysfunction, a field still in its infancy, is largely focused on impaired phagocytosis which is a most important role of these cells. However, defective phagocytosis may just be the tip of the iceberg and it is likely that this emerging interest will reveal even broader compromise of microglial cell functions, which will be important for improved understanding of neurodegenerative disease pathogenesis [31].
Acknowledgements We thank the Cooper family of Indialantic, FL, for their support of dementia research.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest
Neurodegeneration Current Opinion in Immunology
Microglial dysfunction hypothesis. Multiple etiological factors contribute to produce microglial senescent degeneration, which is evident pathologically as cytoplasmic fragmentation. Neuronal tau pathology may occur as a result of microglial senescent dysfunction. www.sciencedirect.com
1.
Najjar S, Pearlman DM, Alper K, Najjar A, Devinsky O: Neuroinflammation and psychiatric illness. J Neuroinflammation 2013, 10:43.
2.
Frick LR, Williams K, Pittenger C: Microglial dysregulation in psychiatric disease. Clin Dev Immunol 2013, 2013:608654. Current Opinion in Immunology 2014, 29:93–96
96 Immune senescence
3.
Streit WJ, Mrak RE, Griffin WS: Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation 2004, 1:14.
4.
Streit WJ, Xue QS: Microglial senescence. CNS Neurol Disord Drug Targets 2013, 12:763-767.
5.
McGeer PL, Itagaki S, Tago H, McGeer EG: Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 1987, 79:195-200.
6.
Rogers J, Luber-Narod J, Styren SD, Civin WH: Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease. Neurobiol Aging 1988, 9:339-349.
7.
McGeer PL, Itagaki S, McGeer EG: Expression of the histocompatibility glycoprotein HLA-DR in neurological disease. Acta Neuropathol 1988, 76:550-557.
8.
Streit WJ: Microglial activation and neuroinflammation in Alzheimer’s disease: a critical examination of recent history. Front Aging Neurosci 2010, 2:22.
9.
Giulian D: Reactive glia as rivals in regulating neuronal survival. Glia 1993, 7:102-110.
10. Giulian D, Haverkamp LJ, Li J, Karshin WL, Yu J, Tom D, Li X, Kirkpatrick JB: Senile plaques stimulate microglia to release a neurotoxin found in Alzheimer brain. Neurochem Int 1995, 27:119-137. 11. McGeer PL, McGeer EG: Inflammation, autotoxicity and Alzheimer disease. Neurobiol Aging 2001, 22:799-809. 12. Smith AM, Dragunow M: The human side of microglia. Trends Neurosci 2014. 13. Graeber MB, Li W, Rodriguez ML: Role of microglia in CNS inflammation. FEBS Lett 2011, 585:3798-3805. 14. Streit WJ, Xue QS, Braak H, Del Tredici K: Presence of severe neuroinflammation does not intensify neurofibrillary degeneration in human brain. Glia 2014, 62:96-105. 15. Arvanitakis Z, Grodstein F, Bienias JL, Schneider JA, Wilson RS, Kelly JF, Evans DA, Bennett DA: Relation of NSAIDs to incident AD, change in cognitive function, and AD pathology. Neurology 2008, 70:2219-2225.
19. Streit WJ: Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 2002, 40:133-139. 20. Streit WJ: Microglia and Alzheimer’s disease pathogenesis. J Neurosci Res 2004, 77:1-8. 21. Neumann H, Kotter MR, Franklin RJ: Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 2009, 132:288-295. 22. Fiala M, Lin J, Ringman J, Kermani-Arab V, Tsao G, Patel A, Lossinsky AS, Graves MC, Gustavson A, Sayre J et al.: Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer’s disease patients. J Alzheimers Dis 2005, 7:221-232. 23. Njie EG, Boelen E, Stassen FR, Steinbusch HW, Borchelt DR, Streit WJ: Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol Aging 2012, 33 195 e191–112. 24. Krabbe G, Halle A, Matyash V, Rinnenthal JL, Eom GD, Bernhardt U, Miller KR, Prokop S, Kettenmann H, Heppner FL: Functional impairment of microglia coincides with Betaamyloid deposition in mice with Alzheimer-like pathology. PLoS One 2013, 8:e60921. 25. Hickman SE, Allison EK: El Khoury J: Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci 2008, 28:8354-8360. 26. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ et al.: Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 2013, 368:107-116. 27. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S et al.: TREM2 variants in Alzheimer’s disease. N Engl J Med 2013, 368:117-127. These authors found significantly more variants of TREM2 in AD patients than in control subjects, suggesting that these gene variants are associated with a higher risk of developing AD. The presence of large numbers of TREM2 variants is consistent with the possibility of dysfunctional microglial phagocytosis. 28. Neumann H, Daly MJ: Variant TREM2 as risk factor for Alzheimer’s disease. N Engl J Med 2013, 368:182-184. The significance of identifying TREM2 variants in AD by two independent research groups is discussed
16. Halliday GM, Shepherd CE, McCann H, Reid WG, Grayson DA, Broe GA, Kril JJ: Effect of anti-inflammatory medications on neuropathological findings in Alzheimer disease. Arch Neurol 2000, 57:831-836.
29. Golde TE, Streit WJ, Chakrabarty P: Alzheimer’s disease risk alleles in TREM2 illuminate innate immunity in Alzheimer’s disease. Alzheimers Res Ther 2013, 5:24.
17. Martin BK, Szekely C, Brandt J, Piantadosi S, Breitner JC, Craft S, Evans D, Green R, Mullan M: Cognitive function over time in the Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT): results of a randomized, controlled trial of naproxen and celecoxib. Arch Neurol 2008, 65:896-905.
30. Gu BJ, Baird PN, Vessey KA, Skarratt KK, Fletcher EL, Fuller SJ, Richardson AJ, Guymer RH, Wiley JS: A rare functional haplotype of the P2RX4 and P2RX7 genes leads to loss of innate phagocytosis and confers increased risk of agerelated macular degeneration. FASEB J 2013, 27: 1479-1487.
18. Streit WJ, Braak H, Xue QS, Bechmann I: Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol 2009, 118:475-485.
Current Opinion in Immunology 2014, 29:93–96
31. Fellner L, Jellinger KA, Wenning GK, Stefanova N: Glial dysfunction in the pathogenesis of alpha-synucleinopathies: emerging concepts. Acta Neuropathol 2011, 121:675-693.
www.sciencedirect.com