Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes

Bliederhaeuser, Corinna; Grozdanov, Veselin; Speidel, Anna; Zondler, Lisa; Ruf, Wolfgang; Bayer, Hanna; Kiechle, Martin; Feiler, Marisa S.; Freischmidt, Axel; Brenner, David A.; Witting, Anke; Hengerer, Bastian; Fändrich, Marcus; Ludolph, Albert C.; Weishaupt, Jochen H.; Gillardon, Frank; Danzer, Karin M

doi:10.1007/s00401-015-1504-2

Cited by 152 publications

(114 citation statements)

References 67 publications

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“…Recently, it could be demonstrated that cultured microglia from adult mice displayed a less efficient uptake and clearance of oligomeric α-synuclein as compared to younger mice. Similar effects could be demonstrated when analyzing peripheral monocytes from older vs. younger human subjects (Bliederhaeuser et al, 2016). Taken together, these findings suggest that there might be an age-dependent deficit in the uptake and clearance of toxic α-synuclein by phagocytic cells.…”

Section: Proposed Mechanisms Behind α-Synuclein Mediated Toxicitysupporting

confidence: 66%

Alpha-Synuclein Oligomers—Neurotoxic Molecules in Parkinson's Disease and Other Lewy Body Disorders

2016

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Adverse intra- and extracellular effects of toxic α-synuclein are believed to be central to the pathogenesis in Parkinson's disease and other disorders with Lewy body pathology in the nervous system. One of the physiological roles of α-synuclein relates to the regulation of neurotransmitter release at the presynapse, although it is still unclear whether this mechanism depends on the action of monomers or smaller oligomers. As for the pathogenicity, accumulating evidence suggest that prefibrillar species, rather than the deposits per se, are responsible for the toxicity in affected cells. In particular, larger oligomers or protofibrils of α-synuclein have been shown to impair protein degradation as well as the function of several organelles, such as the mitochondria and the endoplasmic reticulum. Accumulating evidence further suggest that oligomers/protofibrils may have a toxic effect on the synapse, which may lead to disrupted electrophysiological properties. In addition, recent data indicate that oligomeric α-synuclein species can spread between cells, either as free-floating proteins or via extracellular vesicles, and thereby act as seeds to propagate disease between interconnected brain regions. Taken together, several lines of evidence suggest that α-synuclein have neurotoxic properties and therefore should be an appropriate molecular target for therapeutic intervention in Parkinson's disease and other disorders with Lewy pathology. In this context, immunotherapy with monoclonal antibodies against α-synuclein oligomers/protofibrils should be a particularly attractive treatment option.

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Section: Proposed Mechanisms Behind α-Synuclein Mediated Toxicitysupporting

confidence: 66%

Alpha-Synuclein Oligomers—Neurotoxic Molecules in Parkinson's Disease and Other Lewy Body Disorders

2016

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“…Furthermore, in a mouse model of Alzheimer’s disease, the phagocytic capacity of microglia was reduced and inversely correlated to the Aβ plaque burden, suggesting that microglia function declined with severity of disease (Krabbe et al, 2013). Similar defective phagocytic activity was described in aged mice whereby primary microglia isolated from aged mice had less effectively taken up exosome associated α-synuclein oligomers compared to microglia from young mice (Bliederhaeuser et al, 2015). On the contrary, results from other studies in animal models of PD have suggested long-term phagocytic activation of microglia (Barcia et al, 2013; Rodriguez et al, 2007).…”

Section: Introductionsupporting

confidence: 60%

Microglial phenotypes in Parkinson’s disease and animal models of the disease

Joers

Tansey

Mulas

et al. 2017

Progress in Neurobiology

223

160

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Over the last decade the important concept has emerged that microglia, similar to other tissue macrophages, assume different phenotypes and serve several effector functions, generating the theory that activated microglia can be organized by their pro-inflammatory or anti-inflammatory and repairing functions. Importantly, microglia exist in a heterogenous population and their phenotypes are not permanently polarized into two categories; they exist along a continuum where they acquire different profiles based on their local environment. In Parkinson’s disease (PD), neuroinflammation and microglia activation are considered neuropathological hallmarks, however their precise role in relation to disease progression is not clear, yet represent a critical challenge in the search of disease-modifying strategies. This review will critically address current knowledge on the activation states of microglia as well as microglial phenotypes found in PD and in animal models of PD, focusing on the expression of surface molecules as well as pro-inflammatory and anti-inflammatory cytokine production during the disease process. While human studies have reported an elevation of both pro- or anti-inflammatory markers in the serum and CSF of PD patients, animal models have provided insights on dynamic changes of microglia phenotypes in relation to disease progression especially prior to the development of motor deficits. We also review recent evidence of malfunction at multiple steps of NFκB signaling that may have a causal interrelationship with pathological microglia activation in animal models of PD. Finally, we discuss the immune-modifying strategies that have been explored regarding mechanisms of chronic microglial activation.

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“…This observation might be explained by age-dependent microglia deficits. Indeed, isolated microglia from adult mice display phagocytosis impairment of free and exosome-associated αSyn oligomers associated with enhanced TNFα secretion (Bliederhaeuser et al, 2016). Taken together, the contribution of aged microglia to the progressive nature of PD is most likely and the fact that the nigrostriatal system displays a high density of microglia (Sharaf et al, 2013) further supports the hypothesis that microglia are involved in PD pathogenesis.…”

Section: Aging and Ad And Pdmentioning

confidence: 99%

Aging Microglia—Phenotypes, Functions and Implications for Age-Related Neurodegenerative Diseases

Spittau

2017

Front. Aging Neurosci.

200

161

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Aging of the central nervous system (CNS) is one of the major risk factors for the development of neurodegenerative pathologies such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). The molecular mechanisms underlying the onset of AD and especially PD are not well understood. However, neuroinflammatory responses mediated by microglia as the resident immune cells of the CNS have been reported for both diseases. The unique nature and developmental origin of microglia causing microglial self-renewal and telomere shortening led to the hypothesis that these CNS-specific innate immune cells become senescent. Age-dependent and senescence-driven impairments of microglia functions and responses have been suggested to play essential roles during onset and progression of neurodegenerative diseases. This review article summarizes the current knowledge of microglia phenotypes and functions in the aging CNS and further discusses the implications of these age-dependent microglia changes for the development and progression of AD and PD as the most common neurodegenerative diseases.

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Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes

Cited by 152 publications

References 67 publications

Alpha-Synuclein Oligomers—Neurotoxic Molecules in Parkinson's Disease and Other Lewy Body Disorders

Alpha-Synuclein Oligomers—Neurotoxic Molecules in Parkinson's Disease and Other Lewy Body Disorders

Microglial phenotypes in Parkinson’s disease and animal models of the disease

Aging Microglia—Phenotypes, Functions and Implications for Age-Related Neurodegenerative Diseases

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