“…Genome wide association studies (GWAS) have been useful to highlight genetic risk factors important for PD susceptibility (Sekiyama et al, 2014). Interestingly, the genes most strongly associated with PD (α-synuclein and tau) were already identified in neurodegeneration genetic linkage or genome wide association studies (Golbe et al, 1996, Polymeropoulos et al, 1996, Polymeropoulos et al, 1997, Martin et al, 2001, Zhang et al, 2005a).…”
Section: Genetics Of Pd Relevant To the M1 Activation Statementioning
Parkinson Disease (PD) is a chronic and progressive neurodegenerative disorder of unknown etiology. Autopsy findings, genetics, retrospective studies, and molecular imaging all suggest a role for inflammation in the neurodegenerative process. However, relatively little is understood about the causes and implications of neuroinflammation in PD. Understanding how inflammation arises in PD, in particular the activation state of cells of the innate immune system, may provide an exciting opportunity for novel neuroprotective therapeutics. We analyze the evidence of immune system involvement in PD susceptibility, specifically in the context of M1 and M2 activation states. Tracking and modulating these activation states may provide new insights into both PD etiology and therapeutic strategies.
“…Genome wide association studies (GWAS) have been useful to highlight genetic risk factors important for PD susceptibility (Sekiyama et al, 2014). Interestingly, the genes most strongly associated with PD (α-synuclein and tau) were already identified in neurodegeneration genetic linkage or genome wide association studies (Golbe et al, 1996, Polymeropoulos et al, 1996, Polymeropoulos et al, 1997, Martin et al, 2001, Zhang et al, 2005a).…”
Section: Genetics Of Pd Relevant To the M1 Activation Statementioning
Parkinson Disease (PD) is a chronic and progressive neurodegenerative disorder of unknown etiology. Autopsy findings, genetics, retrospective studies, and molecular imaging all suggest a role for inflammation in the neurodegenerative process. However, relatively little is understood about the causes and implications of neuroinflammation in PD. Understanding how inflammation arises in PD, in particular the activation state of cells of the innate immune system, may provide an exciting opportunity for novel neuroprotective therapeutics. We analyze the evidence of immune system involvement in PD susceptibility, specifically in the context of M1 and M2 activation states. Tracking and modulating these activation states may provide new insights into both PD etiology and therapeutic strategies.
“…These protein aggregates are known as amyloid fibrils; these are highly organised, generally insoluble and rich in b-secondary structure [3]. Alzheimer's disease, Parkinson's disease, type 2 diabetes and cystic fibrosis are some examples of diseases where the deposition of amyloid fibrils is an important component in their pathogenesis [4][5][6][7]. The term amyloid has its origin in the discovery of these aggregates in biopsies and the use of iodine to stain this material.…”
“…52 Thus, it is likely that T2DM may be a common pathogenic contributor which exacerbates many disorders of the central nervous system. 53
Fig. 3Metabolic dysfunctions exacerbate neurodegenerative diseases.…”
Protein aggregation is a pathological hallmark of and may play a central role in the neurotoxicity in age-associated neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. Accordingly, inhibiting aggregation of amyloidogenic proteins, including amyloid β and α-synuclein, has been a main therapeutic target for these disorders. Among various strategies, amyloid β immunotherapy has been extensively investigated in Alzheimer’s disease, followed by similar studies of α-synuclein in Parkinson’s disease. Notably, a recent study of solanezumab, an amyloid β monoclonal antibody, raises hope for the further therapeutic potential of immunotherapy, not only in Alzheimer’s disease, but also for other neurodegenerative disorders, including Parkinson’s disease. Thus, it is expected that further refinement of immunotherapy against neurodegenerative diseases may lead to increasing efficacy. Meanwhile, type II diabetes mellitus has been associated with an increased risk of neurodegenerative disease, such as Alzheimer’s disease and Parkinson’s disease, and studies have shown that metabolic dysfunction and abnormalities surrounding insulin signaling may underlie disease progression. Naturally, “anti-insulin resistance” therapy has emerged as a novel paradigm in the therapy of neurodegenerative diseases. Indeed, incretin agonists, which stimulate pancreatic insulin secretion, reduce dopaminergic neuronal loss and suppress Parkinson’s disease disease progression in clinical trials. Similar studies are ongoing also in Alzheimer’s disease. This paper focuses on critical issues in “immunotherapy” and “anti-insulin resistance” therapy in relation to therapeutic strategies against neurodegenerative disease, and more importantly, how they might merge mechanistically at the point of suppression of protein aggregation, raising the possibility that combined immunotherapy and “anti-insulin resistance” therapy may be superior to either monotherapy.
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