Alzheimer's disease and type 2 diabetes: Two diseases, one common link?

Bartl, Jasmin; Monoranu, Camelia‐Maria; Wagner, Anne-Kristin; Kolter, Jann F.; Riederer, Peter; Grünblatt, Edna

doi:10.3109/15622975.2011.650204

Cited by 16 publications

(5 citation statements)

References 28 publications

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“…Once active, AKT enters the cytoplasm where it leads to the phosphorylation and inactivation of GSK3 (Jolivalt et al, 2008 Consistent with the actual finding reported here, our group could already report that in AD patient less INSR were found especially in the hippocampal region of the brain (Bartl et al, 2012). Not only an impairment of INSR leads to an activation of GSK3β as explained before, also oxidative stress can enhance the activity of this kinase (Hernandez and Avila, 2008).…”

Section: Discussionsupporting

confidence: 79%

Different effects of soluble and aggregated amyloid β42 on gene/protein expression and enzyme activity involved in insulin and APP pathways

et al. 2012

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Although Alzheimer's dementia (AD) is not characterised any longer simply as the accumulation and deposition of amyloid beta (A ) peptides and hyperphosphorylation of tau proteins within the brain, excessive A (42) deposition is still considered to play a major role in this illness. A are able to adopt many differently aggregate forms, including amyloid fibrils as well as nonfibrillar structures (soluble A (42) oligomers). It is not well-established that which A (42) state is most responsible for AD or why. We wanted to verify which effects A (42) oligomers and aggregated peptides have on gene expression, protein level and enzyme activity of insulin and amyloid precursor protein (APP) pathways in vitro. Human neuroblastoma cells (SH-SY5Y) were treated with varying concentrations of soluble and aggregated A (42). Treatment effects on -secretase (BACE), glycogen synthase kinase 3 (GSK3 ), glycogen synthase kinase 3 (GSK3 ), phosphatidylinositol-3 kinase (PI-3K), insulin-degrading enzyme (IDE), insulin-receptor substrate 1 (IRS1), insulin receptor (INSR) and monoamine oxidase B (MAO-B) were investigated via quantitative-PCR, western blot, ELISA and enzyme activity assay. We could find different effects of soluble and aggregated peptides especially on gene/protein expression of GSK3 and INSR and on GSK3 and MAO-B activity. Soluble peptides showed significant effects leading to increased gene expression and protein amount of GSK3 and to decreased level of gene and protein expression of INSR. MAO-B activity was enhanced after treatment with aggregated peptides and strongly inhibited after soluble A (42) treatment. Our data might provide insights into selective effects of specific forms of A (42)

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Section: Discussionsupporting

confidence: 79%

Different effects of soluble and aggregated amyloid β42 on gene/protein expression and enzyme activity involved in insulin and APP pathways

et al. 2012

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“…These pathways involve glycogen synthase-kinase-3 (GSK3) inhibition, via protein kinase B (Akt/PKB) [ 16 , 17 ]. In addition, IR influences the accumulation/degradation of amyloid-β and tau protein, the major neuropathological hallmarks of the memory loss developed in Alzheimer’s disease (AD) [ 13 – 15 ]. We aimed to investigate whether cognitively impaired SHRs develop a central insulin resistance in parallel to the peripheral one, but data published so far on cognitive performance in the SHR model have indicated that measurements were done using different cognitive tests, comparing different control strains, using animals of different ages and not always done using both sexes [ 3 , 18 – 32 ].…”

Section: Introductionmentioning

confidence: 99%

Characterization of cognitive deficits in spontaneously hypertensive rats, accompanied by brain insulin receptor dysfunction

et al. 2015

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BackgroundThe spontaneously hypertensive rat (SHR) has been used to model changes in the central nervous system associated with cognitive-related disorders. Recent human and animal studies indicate a possible relationship between cognitive deficits, insulin resistance and hypertension. We aimed to investigate whether cognitively impaired SHRs develop central and/or peripheral insulin resistance and how their cognitive performance is influenced by the animal’s sex and age as well as strains used for comparison (Wistar and Wistar-Kyoto/WKY).MethodsThree and seven-month-old SHR, Wistar, and WKY rats were studied for their cognitive performance using Morris Water Maze (MWM) and Passive Avoidance tests (PAT). Plasma glucose and insulin were obtained after oral glucose tolerance tests. Cerebral cortex, hippocampus, and striatum status of insulin-receptor (IR) β-subunit and glycogen synthase kinase-3β (GSK3β) and their phosphorylated forms were obtained via ELISA.ResultsSHRs performed poorly in MWM and PAT in comparison to both control strains but more pronouncedly compared to WKY. Females performed poorer than males and 7-month-old SHRs had poorer MWM performance than 3-month-old ones. Although plasma glucose levels remained unchanged, plasma insulin levels were significantly increased in the glucose tolerance test in 7-month-old SHRs. SHRs demonstrated reduced expression and increased activity of IRβ-subunit in cerebral cortex, hippocampus, and striatum with different regional changes in phospho/total GSK3β ratio, as compared to WKYs.ConclusionResults indicate that cognitive deficits in SHRs are accompanied by both central and peripheral insulin dysfunction, thus allowing for the speculation that SHRs might additionally be considered as a model of insulin resistance-induced type of dementia.Electronic supplementary materialThe online version of this article (doi:10.1186/s40303-015-0012-6) contains supplementary material, which is available to authorized users.

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“…Glucose metabolic disorders are probably an initiating factor 1,2. A variety of mechanisms have been postulated in the risk of AD and diabetes mellitus (DM) 3,4. Some scholars have even proposed that AD is type 3 diabetes 5,6.…”

Section: Introductionmentioning

confidence: 99%

Minocycline alleviates beta-amyloid protein and tau pathology via restraining neuroinflammation induced by diabetic metabolic disorder

Cai¹,

Yan²,

Wang³

2013

CIA

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BackgroundCompelling evidence has shown that diabetic metabolic disorder plays a critical role in the pathogenesis of Alzheimer’s disease, including increased expression of β-amyloid protein (Aβ) and tau protein. Evidence has supported that minocycline, a tetracycline derivative, protects against neuroinflammation induced by neurodegenerative disorders or cerebral ischemia. This study has evaluated minocycline influence on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the brain of diabetic rats to clarify neuroprotection by minocycline under diabetic metabolic disorder.MethodAn animal model of diabetes was established by high fat diet and intraperitoneal injection of streptozocin. In this study, we investigated the effect of minocycline on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the hippocampus of diabetic rats via immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay.ResultsThese results showed that minocycline decreased expression of Aβ protein and lowered the phosphorylation of tau protein, and retarded the proinflammatory cytokines, but not amyloid precursor protein.ConclusionOn the basis of the finding that minocycline had no influence on amyloid precursor protein and beta-site amyloid precursor protein cleaving enzyme 1 which determines the speed of Aβ generation, the decreases in Aβ production and tau hyperphosphorylation by minocycline are through inhibiting neuroinflammation, which contributes to Aβ production and tau hyperphosphorylation. Minocycline may also lower the self-perpetuating cycle between neuroinflammation and the pathogenesis of tau and Aβ to act as a neuroprotector. Therefore, the ability of minocycline to modulate inflammatory reactions may be of great importance in the selection of neuroprotective agents, especially in chronic conditions like diabetes and Alzheimer’s disease.

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Alzheimer's disease and type 2 diabetes: Two diseases, one common link?

Cited by 16 publications

References 28 publications

Different effects of soluble and aggregated amyloid β42 on gene/protein expression and enzyme activity involved in insulin and APP pathways

Different effects of soluble and aggregated amyloid β42 on gene/protein expression and enzyme activity involved in insulin and APP pathways

Characterization of cognitive deficits in spontaneously hypertensive rats, accompanied by brain insulin receptor dysfunction

Minocycline alleviates beta-amyloid protein and tau pathology via restraining neuroinflammation induced by diabetic metabolic disorder

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