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Alzheimer's disease And Diabetes: New Insights and Unifying Therapies.

Department of Clinical Science, Section of Biochemistry, School of Medicine. Università Politecnica delle Marche, Via Tronto 10 A, 60020 Ancona, Italy. .
Current diabetes reviews 01/2013; 9(3). DOI: 10.2174/1573399811309030003
Source: PubMed

ABSTRACT Several research groups have begun to associate the Alzheimer Disease (AD) to Diabetes Mellitus (DM), obesity and cardiovascular disease. This relationship is so close that some authors have defined Alzheimer Disease as Type 3 Diabetes. Numerous studies have shown that people with type 2 diabetes have twice the incidence of sporadic AD. Insulin deficiency or insulin resistance facilitates cerebral β-amyloidogenesis in murine model of AD, accompanied by a significant elevation in APP (Amyloid Precursor Protein) and BACE1 (β-site APP Cleaving Enzime 1). Similarly, deposits of Aβ produce a loss of neuronal surface insulin receptors and directly interfere with the insulin signaling pathway. Furthermore, as it is well known, these disorders are both associated to an increased cardiovascular risk and an altered cholesterol metabolism, so we have analyzed several therapies which recently have been suggested as a remedy to treat together AD and DM. The aim of the present review is to better understand the strengths and drawbacks of these therapies.

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Available from: Arianna Vignini, Jul 26, 2015
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    • "Thus, most studies on AD research depend on transgenic models only mutant on APP, PS1 and tau. However, an increasing number of factors, including ApoE4, oxidative stress, aging and insulin resistance, have been found to be related to AD, especially late-onset ( > 60 years) or sporadic AD (Liu et al., 2013; Schraml et al., 2013; Vignini et al., 2013). The investigation of the insulin desensitization in the brains of AD patients adds new information about the progression and origin of the disease. "
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    ABSTRACT: Abstract Alzheimer's disease (AD) is a complex neurodegenerative disorder, which involves many underlying pathological processes. Recently, it has been demonstrated that AD also includes impairments of insulin signaling in the brain. Type 2 diabetes is a risk factor for AD, and AD and diabetes share a number of pathologies. The classical hallmarks of AD are senile plaques and neurofibrillary tangles, which consist of amyloid-β and hyperphosphorylated tau. Based on the two hallmarks, transgenic animal models of AD have been developed, which express mutant human genes of amyloid precursor protein, presenilin-1/2, and tau. It is likely that these mouse models are too limited in their pathology. In this work, we describe mouse models that model diabetes and show insulin signaling impairment as well as neurodegenerative pathologies that are similar to those seen in the brains of AD patients. The combination of traditional AD mouse models with induced insulin impairments in the brain may be a more complete model of AD. Interestingly, AD mouse models treated with drugs that have been developed to cure type 2 diabetes have shown impressive outcomes. Based on these findings, several ongoing clinical trials are testing long lasting insulin analogues or GLP-1 mimetics in patients with AD.
    Reviews in the neurosciences 12/2013; 24(6):607-615. DOI:10.1515/revneuro-2013-0034 · 3.31 Impact Factor
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    • "It is worth noting that one of the risk factors for AD is diabetes mellitus, in which excessive generation of free radicals was may play a major pathogenic role (Lipinski, 2001). This has recently resulted in raising intriguing questions regarding the common denominator in AD and diabetes (Craft, 2012; Adeghate et al., 2013; Vignini et al., 2013). Another factor has been suggested to be involved in the pathogenesis of AD, which is copper known to generate hydroxyl radicals in hypoxia. "
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    Frontiers in Human Neuroscience 10/2013; 7(article 735):735. DOI:10.3389/fnhum.2013.00735 · 2.90 Impact Factor
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    ABSTRACT: The discovery of causative genetic mutations in affected family members has historically dominated our understanding of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Nevertheless, most cases of neurodegenerative disease are not explained by Mendelian inheritance of known genetic variants, but instead are thought to have a complex etiology with numerous genetic and environmental factors contributing to susceptibility. Although unbiased genome-wide association studies (GWAS) have identified novel associations to neurodegenerative diseases, most of these hits explain only modest fractions of disease heritability. In addition, despite the substantial overlap of clinical and pathologic features among major neurodegenerative diseases, surprisingly few GWAS-implicated variants appear to exhibit cross-disease association. These realities suggest limitations of the focus on individual genetic variants and create challenges for the development of diagnostic and therapeutic strategies, which traditionally target an isolated molecule or mechanistic step. Recently, GWAS of complex diseases and traits have focused less on individual susceptibility variants and instead have emphasized the biological pathways and networks revealed by genetic associations. This new paradigm draws on the hypothesis that fundamental disease processes may be influenced on a personalized basis by a combination of variants - some common and others rare, some protective and others deleterious - in key genes and pathways. Here, we review and synthesize the major pathways implicated in neurodegeneration, focusing on GWAS from the most prevalent neurodegenerative disorders, AD and PD. Using literature mining, we also discover a novel regulatory network that is enriched with AD- and PD-associated genes and centered on the SP1 and AP-1 (Jun/Fos) transcription factors. Overall, this pathway- and network-driven model highlights several potential shared mechanisms in AD and PD that will inform future studies of these and other neurodegenerative disorders. These insights also suggest that biomarker and treatment strategies may require simultaneous targeting of multiple components, including some specific to disease stage, in order to assess and modulate neurodegeneration. Pathways and networks will provide ideal vehicles for integrating relevant findings from GWAS and other modalities to enhance clinical translation.
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