Diabetes and Alzheimer Disease, Two Overlapping Pathologies with the Same Background: Oxidative Stress

Rosales-Corral, Sergio; Tan, Dun Xian; Manchester, Lucien C.; Reíter, Russel J.

doi:10.1155/2015/985845

Cited by 109 publications

(63 citation statements)

References 132 publications

(160 reference statements)

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“…Insulin resistance, hyperinsulinemia, and hyperglycemia can promote the onset of AD (Rönnemaa et al 2008;de Oliveira Lanna et al 2014) by accelerating tau phosphorylation and neuritic plaque formation (Bitel et al 2012;Matsuzaki et al 2010) and, overlapping with AD pathology, aggravate the progression of neurodegeneration due to OS, mitochondrial dysfunction, neuroinflammation, etc. as a common background (Carvalho et al 2015;Kraska et al 2012;RorizFilho et al 2009;Rosales-Corral et al 2015). Thus, impaired insulin signaling may be a possible link between AD and DM (Jellinger 2015a, b;Sato et al 2011).…”

Section: Pathologymentioning

confidence: 99%

The diabetic brain and cognition

et al. 2017

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The prevalence of both Alzheimer's disease (AD) and vascular dementia (VaD) is increasing with the aging of the population. Studies from the last several years have shown that people with diabetes have an increased risk for dementia and cognitive impairment. Therefore, the authors of this consensus review tried to elaborate on the role of diabetes, especially diabetes type 2 (T2DM) in both AD and VaD. Based on the clinical and experimental work of scientists from 18 countries participating in the International Congress on Vascular Disorders and on literature search using PUBMED, it can be concluded that T2DM is a risk factor for both, AD and VaD, based on a pathology of glucose utilization. This pathology is the consequence of a disturbance of insulin-related mechanisms leading to brain insulin resistance. Although the underlying pathological mechanisms for AD and VaD are different in many aspects, the contribution of T2DM and insulin resistant brain state (IRBS) to cerebrovascular disturbances in both disorders

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Section: Pathologymentioning

confidence: 99%

The diabetic brain and cognition

et al. 2017

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“…Overlapping with AD pathology, they aggravate the progression of neurodegeneration due to oxidative stress, disordered control of protein translation, neurotoxicity by Advanced Glycation End-Products (AGE), mitochondrial dysfunction, neuroinflammation, and a variety of other mechanisms as common pathogenic backgroud culminating in synaptic dysfunction and memory loss [16,26,[39][40][41][42][43][44]. Recent research data indicate that there is a widespread conformational change in the protein control and other molecular mechanisms involved in both AD and DMT2 that form β-sheet like motifs, interacting with other proteins and consequently catalyzing their translation into the toxic state may lead to neurodegeneration and also to cerebral hypoperfusion, which result in dysfunction and degeneration of neuroglial cells and myelin components [45,46].…”

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confidence: 99%

The Diabetic Brain and Dementia

Jellinger¹

2015

J Alzheimers Dis Parkinsonism

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Alzheimer's Disease (AD) and Diabetes Mellitus (DM) are the two most common and devastating health problems in the elderly. They share a number of common features among which are important impact on quality of life and substantial health care costs. Epidemiological and biological evidence support a pathophysiological link between Type 2 Diabetes Mellitus (DMT2) and cognitive impairment [1][2][3]. A causative association between DM and Alzheimer's disease has been suggested on the basis of clinical, epidemiological, genetic and experimental studies [2,[4][5][6][7][8][9]. Persons with DM have a higher incidence of cognitive decline and an increased risk of developing AD and other types of dementia, and comorbidity increases the risk [10,11]. Insulin resistance predicts medial temporal hypermetabolism in Mild Cognitive Impairment (MCI) conversion to AD [12] and glucose uptake changes in AD in medial temporal regions predicting worse memory performance [13]. DM has been shown to influence the rate of functional decline among patients with mild AD dementia than in those without comorbid DM [14]. However, the precise mechanisms involved in the development of AD in diabetics are not yet fully understood, and several pathogenic pathways have been discussed [3,4,[15][16][17][18][19][20].Autopsy studies stated that diabetic patients show significantly less AD pathology (senile plaques, neurofibrillary tangles, cerebral amyloid angiopathy, etc.) but more cerebrovascular lesions including microvascular lesions and white matter changes than subjects without DM [5,[21][22][23][24][25][26][27]. Vasculo-neural dysfunction has been suggested to represent a potential etiological linkage between DMT2 and AD [6,28], while others suggested that the association between DM and dementia is only partially mediated through cerebrovascular disease and that DM is associated independently with overal dementia among elderly, but not with AD or vascular dementia [29].Positive DMT2 status appears to exacerbate AD pathology in the presence of ApoE ε4 [30]. Although insulin mitigates Aβ deposition and hyperphosphorylation of tau [17,31], DM in combination with ApoE ε4 may lead to excessive phosphorylation of tau [32], but only in subjects with late stage AD [21]. DM modifies metabolism of Aβ and tau causing Aβ/tau-dependent pathological changes, although there is evidence that suggests an interaction of Aβ/tau-dependent and -independent mechanisms [31]. Evidence supports insulin's role in cognition, synaptic remodelling and facilitation of memory [33]. On the other hand, insulin has been shown to modulate the level of Aβ, to protect neurons against detrimental effects of Aβ on synapses [33]. It further facilitates reduction of amyloid plaques, downregulation of Aβ-derived diffusible ligand-binding sites and also to promote tau hypophosphorylation, which stabilizes microtubules. These data and the observation that the combination of insulin and other antidiabetic medication is associated with lower neuritic plaque density [23,34] are providing a...

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“…Insulin resistance leads to type-2 diabetes mellitus (T2DM), an important risk factor in AD development that is associated with impaired insulin signaling and glucose metabolism [480,481,548]. A growing body of experimental and clinical research provides evidence that both AD and T2DM share many pathophysiological symptoms, indicating that drugs used for T2DM treatment also may alleviate AD symptoms [1,[49][50][51][52].…”

Section: Chapter # Vii: Metformin Attenuates Aβ Pathology Mediated Thmentioning

confidence: 99%

“…As several studies observe similar pathways involved in both AD and type 2 diabetes mellitus (T2DM), one possibility is that drugs used for T2DM treatment may prevent AD or at least alleviate symptoms [1,[49][50][51][52].…”

Section: Chapter # I: General Introductionmentioning

confidence: 99%

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Metabolic study of Alzheimer’s disease using mutant C. elegans

Ahmad¹

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Alzheimer's disease (AD) is associated with chronic neurodegeneration and is the cause of the most common form of dementia. The main hallmarks of AD are aggregates of amyloid beta (Aβ) and formation of hyperphosphorylated tau neurofibrillary tangles (NFTs). Unfortunately, after more than 100 years of research the exact cause(s) and mechanisms involved in AD progression remain unclarified. Evidence indicates that impaired mitochondrial bioenergetics may precede by decades, the neurodegeneration and cognitive decline associated with AD. Moreover, a genetic association of the core metabolic enzyme dihydrolipoamide dehydrogenase (DLD) with late-onset AD and reduced activity of DLD-containing enzymes suggests glucose hypo-metabolism as a possible cause of AD. Contrary to this, improvements of AD symptoms under caloric restriction or other means of reducing-glucose dependent energy metabolism supports an alternative hypothesis that a decrease in glucose metabolism may be protective. In the present study, we used mutant Caenorhabditis elegans (C. elegans) to investigate the effect of glucose metabolism on AD progression. We initially looked at the role of suppressed DLD-1, and then we focused on the effect of high glucose in AD pathogenesis.Transgenic expression of Aβ in C. elegans causes both phenotypic and behavioral defects and results in accumulation of toxic Aβ oligomers, culminating in protein aggregation as is normally associated with AD pathophysiology. Aβ expression in worm muscle causes agedependent progressive paralysis and impaired acetylcholine neurotransmission while neuronal Aβ expression results in defective chemotaxis and impaired serotonin sensitivity as well as reduced fecundity and egg hatching. Suppression of the dld-1 gene alleviated paralysis, improved acetylcholine neurotransmission, enhanced chemotaxis and restored normal sensitivity to serotonin.dld-1 gene suppression also protects vitality as indicated by improved fecundity and egg hatching.Interestingly, protective effects of dld-1 suppression could be reversed using the calcium ionophore (CaI), indicating that the protective mechanism involves calcium signaling. Each of these beneficial effects of dld-1 gene suppression could be mimicked using a specific, small molecule inhibitor of the DLD-1 enzyme, 5-methoxyindole-2-carboxylic acid (MICA).High glucose levels are associated with the metabolic disorder, diabetes, which is a major risk factor for AD. In fact, it has been suggested that AD is a neural form of diabetes, type 3 diabetes. If true, drugs used to treat diabetes could act as possible treatments for AD. In this study, I investigated the effect of elevated glucose, the glucose metabolism inhibitor, 2-deoxy-d-glucose ii (2DOG) as well as the anti-diabetes drugs, metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), on AD progression. Elevated glucose in the growth medium induced hyperactivity, which interfered with the paralysis assays, but it was seen to impair cholinergic neurotransmission, egg laying and hatc...

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Diabetes and Alzheimer Disease, Two Overlapping Pathologies with the Same Background: Oxidative Stress

Cited by 109 publications

References 132 publications

The diabetic brain and cognition

The diabetic brain and cognition

The Diabetic Brain and Dementia

Metabolic study of Alzheimer’s disease using mutant C. elegans

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