The Link Between Diabetes Mellitus and Tau Hyperphosphorylation: Implications for Risk of Alzheimer's Disease

Hobday, Amy; Parmar, Mayur

doi:10.7759/cureus.18362

Cited by 19 publications

(17 citation statements)

References 40 publications

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“…In addition, we saw increased Tau levels in the hippocampus in T2D which is in line with Hobday et al [45] results. AMPK/GSK-3β pathway dysfunction is considered as the main reason for increased Tau accumulation because of increased GSK-3β activity which nally leads to its hyper-phosphorylation [46].…”

Section: Discussionsupporting

confidence: 93%

High-intensity interval training ameliorate diabetes-induced disturbances in Alzheimer's-related factors in the hippocampus through adiponectin signaling

Khoramipour

Bejeshk

Rajizadeh

et al. 2022

Preprint

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Objectives: Alzheimer’s disease (AD) is closely related to type 2 diabetes (T2D). This study investigated the impact of High-intensity interval training (HIIT) on diabetes-induced disturbances in AD-related factors (including AMP-activated protein kinase (AMPK), Glycogen synthase kinase-3β (GSK3β), and Tau protein) in the hippocampus, with the main focus on adiponectin signaling. Methods: 40 male Wistar rats at the age of 8 weekd were randomly assigned to four groups: control (Con), type 2 diabetes (T2D), HIIT (Ex), and type 2 diabetes + HIIT (T2D+Ex). T2D was induced by high-fat diet plus a single dose of Streptozotocin (STZ). Rats in Ex and T2D+Ex groups performed eight weeks of HIIT (running at 80-95% of Vmax, 4-10 intervals). Insulin and adiponectin levels in serum and hippocampus were measured along with hippocampal expression of insulin and adiponectin receptors, AMPK, GSK3β, and Tau. Homeostasis model assessment for Insulin Resistance (HOMA-IR), Homeostasis model assessment for Insulin Resistance Beta (HOMA-β), and quantitative insulin sensitivity check index (QUICKI) were calculated to assess insulin resistance and sensitivity. Results: T2D decreased insulin and adiponectin levels in serum and hippocampus as well as the hippocampal levels of insulin and adiponectin receptors and AMKP but increased GSK3β and Tau in the hippocampus. HIIT reversed diabetes-induced impairments and consequently decreased Tau accumulation in the hippocampus of diabetic rats. HOMA-IR, HOMA-β, and QUICKI were improved in Ex and T2D+Ex groups. Conclusion: Overall, our results confirmed that T2D has undesirable effects on the levels of some Alzheimer's-related factors in the hippocampus and HIIT could ameliorate these impairments in the hippocampus.

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Section: Discussionsupporting

confidence: 93%

High-intensity interval training ameliorate diabetes-induced disturbances in Alzheimer's-related factors in the hippocampus through adiponectin signaling

Khoramipour

Bejeshk

Rajizadeh

et al. 2022

Preprint

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“…The accumulation of Aβ leads to the development of AD. IGF signaling activation promotes amyloid-protein precursor (APP-A) trafficking, as well as the accumulation of amyloid processing, tau phosphorylation, and a reduction in cerebral blood flow [ 41 ]. IRs are transmembrane receptors and are made with alpha and beta subunits.…”

Section: T2dm and Dementiamentioning

confidence: 99%

“…IR decreases AKT activity, which inhibits GSK-3 and causes tau protein to be hyperphosphorylated [ 43 ]. AKT signaling regulates various responses at the cellular level, such as glycogen synthase kinase-3 beta (GSK3) neuronal survival and TAU phosphorylation [ 41 ]. Increasing the synthesis of GSK3β may alter the post-translational modifications in MAPs (microtubule-associated proteins), such as tau protein [ 41 ].…”

Section: T2dm and Dementiamentioning

confidence: 99%

Development of Dementia in Type 2 Diabetes Patients: Mechanisms of Insulin Resistance and Antidiabetic Drug Development

Singh

Shati

Alfaifi

et al. 2022

Cells

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Dementia is reported to be common in those with type 2 diabetes mellitus. Type 2 diabetes contributes to common molecular mechanisms and an underlying pathology with dementia. Brain cells becoming resistant to insulin leads to elevated blood glucose levels, impaired synaptic plasticity, microglial overactivation, mitochondrial dysfunction, neuronal apoptosis, nutrient deprivation, TAU (Tubulin-Associated Unit) phosphorylation, and cholinergic dysfunction. If insulin has neuroprotective properties, insulin resistance may interfere with those properties. Risk factors have a significant impact on the development of diseases, such as diabetes, obesity, stroke, and other conditions. Analysis of risk factors of importance for the association between diabetes and dementia is important because they may impede clinical management and early diagnosis. We discuss the pathological and physiological mechanisms behind the association between Type 2 diabetes mellitus and dementia, such as insulin resistance, insulin signaling, and sporadic forms of dementia; the relationship between insulin receptor activation and TAU phosphorylation; dementia and mRNA expression and downregulation of related receptors; neural modulation due to insulin secretion and glucose homeostasis; and neuronal apoptosis due to insulin resistance and Type 2 diabetes mellitus. Addressing these factors will offer clinical outcome-based insights into the mechanisms and connection between patients with type 2 diabetes and cognitive impairment. Furthermore, we will explore the role of brain insulin resistance and evidence for anti-diabetic drugs in the prevention of dementia risk in type 2 diabetes.

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“…The association between hyperglycemia and AD via tau hyperphosphorylation has been demonstrated [ 17 ]. In addition, inflammation is regarded as a major driver of IR in AD, impairing the blood–brain barrier [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

High sensitivity C-reactive protein and glycated hemoglobin levels as dominant predictors of all-cause dementia: a nationwide population-based cohort study

et al. 2022

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Background Chronic inflammation might play a major role in the pathogenesis linking diabetes mellitus (DM) to cognition. In addition, DM might be the main driver of dementia risk. The purpose of the present study was to evaluate whether inflammation, glycation, or both are associated with the risk of developing all-cause dementia (ACD). Methods A nationwide population-based cohort study was conducted with 4113 participants. The data were obtained from the Taiwanese Survey on Prevalence of Hypertension, Hyperglycemia, and Hyperlipidemia (TwSHHH) in 2007, which was linked with the Taiwan National Health Insurance Research Database (NHIRD). The markers of inflammation, expressed as hs-CRP, and glycation, presented as HbA1c, were measured. High levels of hs-CRP and HbA1c were defined as values greater than or equal to the 66th percentile. Developed ACD was identified based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Results During 32,926.90 person-years, 106 individuals developed ACD in up to 8 years of follow-up. The study participants were separated into four categories by the top tertiles of hs-CRP and HbA1c based on the 66th percentile: high levels of both hs-CRP and HbA1c, only high levels of hs-CRP, only high levels of HbA1c, and non-high levels of hs-CRP nor HbA1c. Those who with a high level of only hs-CRP had the higher hazard for developing ACD (adjusted HR = 2.58; 95% CI = 1.29 ~ 5.17; P = 0.007), followed by the group with a high level of only HbA1c (adjusted HR = 2.52; 95% CI = 1.34 ~ 4.74; P = 0.004) and the group with high levels of both hs-CRP and HbA1c (adjusted HR = 2.36; 95% CI = 1.20 ~ 4.62; P = 0.012). Among those aged less than 65 years, hs-CRP was the only significant predictor of ACD risk (P = 0.046), whereas it did not yield any significant result in the elderly. Conclusions A higher risk of developing ACD was found not only in patients with high levels of inflammation but also high levels of glycated hemoglobin. Future studies should focus on the clinical implementation of hs-CRP or HbA1c to monitor cognitive deficits.

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The Link Between Diabetes Mellitus and Tau Hyperphosphorylation: Implications for Risk of Alzheimer's Disease

Cited by 19 publications

References 40 publications

High-intensity interval training ameliorate diabetes-induced disturbances in Alzheimer's-related factors in the hippocampus through adiponectin signaling

High-intensity interval training ameliorate diabetes-induced disturbances in Alzheimer's-related factors in the hippocampus through adiponectin signaling

Development of Dementia in Type 2 Diabetes Patients: Mechanisms of Insulin Resistance and Antidiabetic Drug Development

High sensitivity C-reactive protein and glycated hemoglobin levels as dominant predictors of all-cause dementia: a nationwide population-based cohort study

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