Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia

Grathwohl, Stefan; Kälin, Roland E.; Bolmont, Tristan; Prokop, Stefan; Winkelmann, Georg; Kaeser, Stephan A.; Odenthal, Jörg; Radde, Rebecca; Eldh, T.; Gandy, SE; Aguzzi, Adriano; Staufenbiel, M; Mathews, Paul M.; Wolburg, Hartwig; Heppner, Frank L.; Jucker, M.

doi:10.1515/nf-2010-0107

Cited by 98 publications

(115 citation statements)

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“…A similar beneficial effect of microglia in stroke was reported in a study where there was a 60 % increase in infarct size by selective elimination of microglia, which the effect was reversed by repopulating the cells [65]. In contrast, microglia ablation was either protective or had no effect in models of other neurodegenerative diseases, including Alzheimer's disease [66], amyotrophic lateral sclerosis [67], and experimental autoimmune encephalomyelitis [68].…”

Section: Microgliasupporting

confidence: 64%

Microglia and Monocyte-Derived Macrophages in Stroke

2016

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Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood-brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood-brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions.

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Section: Microgliasupporting

confidence: 64%

Microglia and Monocyte-Derived Macrophages in Stroke

2016

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“…66 Anti-Ab immunization was successful at reducing plaque deposition in AD mouse models and in the handful of human patients who have come to autopsy, but substantial clinical benefit or at least stabilization of cognitive decline has not been observed. 67e69 This has led to the postulate that antibody-mediated plaque removal in patients with established disease (ie, mild-to-moderate dementia) might be too late, because plaques may not contribute substantially to cognitive impairment during the symptomatic stages of dementia.…”

Section: Plaque Toxicity Accrues Over Time In Admentioning

confidence: 99%

Plaque-Associated Local Toxicity Increases over the Clinical Course of Alzheimer Disease

Serrano-Pozo

Betensky

Frosch

et al. 2016

The American Journal of Pathology

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Amyloid (senile) plaques, one of the two pathologic hallmarks of Alzheimer disease (AD), are associated with dystrophic neurites and glial responses, both astrocytic and microglial. Although plaque burden remains relatively stable through the clinical course of AD, whether these features of local plaque toxicity continue to worsen over the course of the disease is unclear. We performed an unbiased plaque-centered quantification of SMI312 þ dystrophic neurites, GFAP þ reactive astrocytes, and IBA1 þ and CD68 þ activated microglia in randomly selected dense-core (Thioflavin-S þ ) plaques from the temporal neocortex of 40 AD subjects with a symptom duration ranging from 4 to 20 years, and nine nondemented control subjects with dense-core plaques. Dystrophic neurites (Kendall t Z 0.34, P Z 0.001), reactive astrocytes (Kendall t Z 0.30, P Z 0.003), and CD68 þ (Kendall t Z 0.48, P < 0.0001), but not IBA1 microglia (Kendall t Z 0.045, P Z 0.655), exhibited a significant positive correlation with symptom duration. When excluding control subjects, only the positive association between CD68 þ microglia and symptom duration remained significant (Kendall t Z 0.39, P Z 0.0003). The presence of the APOEε4 allele did not affect these results. We conclude that plaques exert an increasing toxicity in the surrounding neuropil over the clinical course of AD, thereby potentially contributing to cognitive decline. (Am J Pathol 2016, 186: 375e384; http://dx

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“…99 Indeed, Aβ deposition occurs efficiently in the near absence of microglia. 100 Nevertheless, considerable evidence indicates that activated microglia and their products are detrimental in many experimental models and natural disease states. It is likely that microglia could contribute to Aβ removal while simultaneously producing agents that are detrimental to neurological structure/function and conducive to progression of pathology.…”

mentioning

confidence: 99%

Neuroinflammatory Cytokines—The Common Thread in Alzheimer Pathogenesis

Griffin¹,

Barger²

2010

US Neurology

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This article discusses the potential role of the cytokine cycle and its corollary as drivers of the relentless progression of Alzheimer's neuropathologies, whether they are the result of gene mutations, gene polymorphisms, and/or environmental and comorbid conditions. Based on the discovery of cytokine overexpression as an accompaniment to the dementia-related glial activation, the cytokine hypothesis wasproposed. This states that in response to the negative impact on neurons of known and unknown risk factors-which include genetic inheritance, comorbid and environmental factors-microglia and astrocytes become activated and produce excess amounts of the immune-modulating cytokine interleukin-1 (IL-1) and the neuritogenic cytokine S100B, respectively. Finding that these glial events occur in fetuses and neonates with Down syndrome provided the first evidence that productive immune responses by activated glia precede rather than follow overt AD-related pathology. This finding can be added to the demonstration of IL-1 induction of amyloid β (Aβ) precursor protein and astrocyte activation with excess production of neuritogenic factor S100B. This combination suggests that IL-1 and S100B overexpression would favor the Aβ production and dystrophic neurite growth necessary for laying down neuritic Aβ plaques. This, together with demonstration of IL-1 induction of excessive production of the precursors of other features common in AD prompted a corollary to the cytokine hypothesis. The corollary states that regardless of the primary cause of the neuronal insult, the result will be chronic glial activation, which in turn will result in further neuronal injury, still more glial activation with excess cytokine expression and so on. This article discusses known causes, genetic and environmental risk factors, and comorbid conditions, and the potential contribution of glial activation with excessive cytokine expression to each. KeywordsAlzheimer's disease (AD), amyloid β (Aβ), apolipoprotein E (ApoE), β−amyloid precursor protein (βAPP), cytokines, Down syndrome (DS), excitotoxicity, glutamate, interleukin-1 (IL-1), S100B, tumor necrosis factor alpha (TNFα) Disclosure: The authors have no conflicts of interest to declare. Acknowledgments:Much of the work cited in this article was supported by National Institutes of Health (NIH) grants P01AG12411 (to WSTG) and R01AG17498 (to SWB). The authors thank Orwa Aboud, MD, for helpful comments and editing. A progression of these neuropathological events seems apparent. For example, the plethora of Aβ plaques at end stages-from several to many-and an inclusion of neurofibrillary tangles-in a few to numerous neurons-strongly suggests that these neuropathological Received

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Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia

Cited by 98 publications

References 0 publications

Microglia and Monocyte-Derived Macrophages in Stroke

Microglia and Monocyte-Derived Macrophages in Stroke

Plaque-Associated Local Toxicity Increases over the Clinical Course of Alzheimer Disease

Neuroinflammatory Cytokines—The Common Thread in Alzheimer Pathogenesis

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