Type 2 diabetes mellitus in the pathophysiology of Alzheimer's disease

Nazareth, Aparecida Marcelino de

doi:10.1590/1980-57642016dn11-020002

Cited by 50 publications

(33 citation statements)

References 97 publications

(136 reference statements)

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“…Insulin resistance, which is a hallmark of type 2 diabetes, has a strong relationship to low‐grade, sterile inflammation, as shown, for example, by substantial upregulation of IL‐6, and activation of the NLRP3 inflammasome . Whether brain insulin resistance has consequences similar to those in type 2 diabetes, or whether it may represent a separate type of pathology referred to as type 3 diabetes, remains to be a matter of debate. Recently, effects of hyperinsulinemia were reported concerning the clearance of Aβ peptides over the blood‐brain barrier, however, with divergent results in Aβ 1‐40 and Aβ 1‐42 , details that will need further clarification with regard to their pathological consequences.…”

Section: Melatonin and Inflammation In Neurodegenerative Diseasesmentioning

confidence: 99%

Melatonin and inflammation—Story of a double‐edged blade

Hardeland

2018

Journal of Pineal Research

343

350

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Melatonin is an immune modulator that displays both pro‐ and anti‐inflammatory properties. Proinflammatory actions, which are well documented by many studies in isolated cells or leukocyte‐derived cell lines, can be assumed to enhance the resistance against pathogens. However, they can be detrimental in autoimmune diseases. Anti‐inflammatory actions are of particular medicinal interest, because they are observed in high‐grade inflammation such as sepsis, ischemia/reperfusion, and brain injury, and also in low‐grade inflammation during aging and in neurodegenerative diseases. The mechanisms contributing to anti‐inflammatory effects are manifold and comprise various pathways of secondary signaling. These include numerous antioxidant effects, downregulation of inducible and inhibition of neuronal NO synthases, downregulation of cyclooxygenase‐2, inhibition of high‐mobility group box‐1 signaling and toll‐like receptor‐4 activation, prevention of inflammasome NLRP3 activation, inhibition of NF‐κB activation and upregulation of nuclear factor erythroid 2‐related factor 2 (Nrf2). These effects are also reflected by downregulation of proinflammatory and upregulation of anti‐inflammatory cytokines. Proinflammatory actions of amyloid‐β peptides are reduced by enhancing α‐secretase and inhibition of β‐ and γ‐secretases. A particular role in melatonin's actions seems to be associated with the upregulation of sirtuin‐1 (SIRT1), which shares various effects known from melatonin and additionally interferes with the signaling by the mechanistic target of rapamycin (mTOR) and Notch, and reduces the expression of the proinflammatory lncRNA‐CCL2. The conclusion on a partial mediation by SIRT1 is supported by repeatedly observed inhibitions of melatonin effects by sirtuin inhibitors or knockdown.

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Section: Melatonin and Inflammation In Neurodegenerative Diseasesmentioning

confidence: 99%

Melatonin and inflammation—Story of a double‐edged blade

Hardeland

2018

Journal of Pineal Research

343

350

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“…These conflicting results suggest that NSAIDs do not improve AD pathogenesis directly in the brain, but that systemic inflammation, such as that seen with rheumatoid arthritis, might affect the brain pathologically. Recent evidence also suggests that inflammatory diseases, such as osteoporosis, diabetes, cancer and infection, are possibly implicated in brain disorders, and that these diseases could affect brain function through immune responses elicited in the periphery; that is, through neuroimmune communication. Furthermore, treatment strategies against such diseases might influence brain function and the macroenvironment, as reported for cancer‐related cognitive impairment or HIV‐associated neurocognitive disorder, possibly leading to the onset of brain disorders.…”

Section: Neuroinflammation and The Interaction Between Brain And Perimentioning

confidence: 99%

Neuroinflammation in mouse models of Alzheimer's disease

Saito

Saido

2018

Clinical & Exp Neuroim

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Alzheimer's disease (AD) is the most common type of neurocognitive disorder. Although both amyloid β peptide deposition and neurofibrillary tangle formation in the AD brain have been established as pathological hallmarks of the disease, many other factors contribute in a complex manner to the pathogenesis of AD before clinical symptoms of the disease become apparent. Longitudinal pathophysiological processes cause patients’ brains to exist in a state of chronic neuroinflammation, with glial cells acting as key regulators of the neuroinflammatory state. However, the detailed molecular and cellular mechanisms of glial function underlying AD pathogenesis remain elusive. Furthermore, recent studies have shown that peripheral inflammatory conditions affect glial cells in the brain through a process of neuroimmune communication. Such disease complexities make it difficult for the pathogenesis of AD to be understood, and impede the development of effective therapeutic strategies to combat the disease. Relevant AD animal models are thus likely to serve as a key resource to overcome many of these issues. Furthermore, as the pathogenesis of AD might be linked to conditions both within the brain as well as peripherally, it might become necessary for AD to be studied as a whole‐body disorder. The present review aimed to summarize insights regarding current AD research, and share perspectives for understanding glial function in the context of the pathogenesis of AD.

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“…Management of Type 2 Diabetes Mellitus (T2DM) is also an important AD prevention strategy (76). A meta-analysis reported that four out of five studies evaluating the association between T2DM and APOE ε4 carrier status on AD risk had positive associations and three were statistically significant, with odds ratios that ranged from 2.4-5.0 (77).…”

Section: Ad Comorbidity Considerationsmentioning

confidence: 99%

Clinical Application of Apoe in Alzheimer’s Prevention: A Precision Medicine Approach

et al. 2018

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Population-attributable risk models estimate that up to one-third of Alzheimer’s disease (AD) cases may be preventable through risk factor modification. The field of AD prevention has largely focused on addressing these factors through universal risk reduction strategies for the general population. However, targeting these strategies in a clinical precision medicine fashion, including the use of genetic risk factors, allows for potentially greater impact on AD risk reduction. Apolipoprotein E (APOE), and specifically the APOE ε4 variant, is one of the most well-established genetic influencers on late-onset AD risk. In this review, we evaluate the impact of APOE ε4 carrier status on AD prevention interventions, including lifestyle, nutrigenomic, pharmacogenomic, AD comorbidities, and other biological and behavioral considerations. Using a clinical precision medicine strategy that incorporates APOE ε4 carrier status may provide a highly targeted and distinct approach to AD prevention with greater potential for success.

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Type 2 diabetes mellitus in the pathophysiology of Alzheimer's disease

Cited by 50 publications

References 97 publications

Melatonin and inflammation—Story of a double‐edged blade

Melatonin and inflammation—Story of a double‐edged blade

Neuroinflammation in mouse models of Alzheimer's disease

Clinical Application of Apoe in Alzheimer’s Prevention: A Precision Medicine Approach

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