Is Alzheimer’s a Disorder of Ageing and Why Don’t Mice get it? The Centrality of Insulin Signalling to Alzheimer’s Disease Pathology

In the last two decades, numerous in vitro studies demonstrated that insulin receptors and theirs downstream pathways are widely distributed throughout the brain. This evidence has proven that; at variance with previous believes; insulin/insulin-like-growth-factor (IGF) signalling plays a crucial role in the regulation of different central nervous system (CNS) tasks. The most important of these functions include: synaptic formation; neuronal plasticity; learning; memory; neuronal stem cell activation; neurite growth and repair. Therefore; dysfunction at different levels of insulin signalling and metabolism can contribute to the development of a number of brain disorders. Growing evidences demonstrate a close relationship between Type 2 Diabetes Mellitus (T2DM) and neurodegenerative disorders such as Alzheimer’s disease. They, in fact, share many pathophysiological characteristics comprising impaired insulin sensitivity, amyloid β accumulation, tau hyper-phosphorylation, brain vasculopathy, inflammation and oxidative stress. In this article, we will review the clinical and experimental evidences linking insulin resistance, T2DM and neurodegeneration, with the objective to specifically focus on insulin signalling-related mechanisms. We will also evaluate the pharmacological strategies targeting T2DM as potential therapeutic tools in patients with cognitive impairment.

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Inflammation and Oxidative Stress: The Molecular Connectivity between Insulin Resistance, Obesity, and Alzheimer’s Disease

Mediators of Inflammation ◽

10.1155/2015/105828 ◽

2015 ◽

Vol 2015 ◽

pp. 1-17 ◽

Cited By ~ 184

Author(s):

Giuseppe Verdile ◽

Kevin N. Keane ◽

Vinicius F. Cruzat ◽

Sandra Medic ◽

Miheer Sabale ◽

...

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Insulin Signalling ◽

Contributory Factor ◽

Protein Accumulation ◽

Age Related ◽

Impaired Insulin ◽

And Oxidative Stress

Type 2 diabetes (T2DM), Alzheimer’s disease (AD), and insulin resistance are age-related conditions and increased prevalence is of public concern. Recent research has provided evidence that insulin resistance and impaired insulin signalling may be a contributory factor to the progression of diabetes, dementia, and other neurological disorders. Alzheimer’s disease (AD) is the most common subtype of dementia. Reduced release (for T2DM) and decreased action of insulin are central to the development and progression of both T2DM and AD. A literature search was conducted to identify molecular commonalities between obesity, diabetes, and AD. Insulin resistance affects many tissues and organs, either through impaired insulin signalling or through aberrant changes in both glucose and lipid (cholesterol and triacylglycerol) metabolism and concentrations in the blood. Although epidemiological and biological evidence has highlighted an increased incidence of cognitive decline and AD in patients with T2DM, the common molecular basis of cell and tissue dysfunction is rapidly gaining recognition. As a cause or consequence, the chronic inflammatory response and oxidative stress associated with T2DM, amyloid-β(Aβ) protein accumulation, and mitochondrial dysfunction link T2DM and AD.

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Agmatine ameliorates type 2 diabetes induced-Alzheimer's disease-like alterations in high-fat diet-fed mice via reactivation of blunted insulin signalling

Neuropharmacology ◽

10.1016/j.neuropharm.2016.10.029 ◽

2017 ◽

Vol 113 ◽

pp. 467-479 ◽

Cited By ~ 44

Author(s):

Somang Kang ◽

Chul-Hoon Kim ◽

Hosung Jung ◽

Eosu Kim ◽

Ho-Taek Song ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Type 2 Diabetes ◽

Alzheimer's Disease ◽

High Fat Diet ◽

Insulin Signalling ◽

High Fat

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Diabetes as a risk factor for Alzheimer's disease: insulin signalling impairment in the brain as an alternative model of Alzheimer's disease

Biochemical Society Transactions ◽

10.1042/bst0390891 ◽

2011 ◽

Vol 39 (4) ◽

pp. 891-897 ◽

Cited By ~ 91

Author(s):

Christian Hölscher

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Risk Factor ◽

Growth Factors ◽

Growth Factor ◽

Insulin Signalling ◽

Cell Signalling ◽

Insulin Receptors ◽

Model Of Alzheimer’S Disease ◽

The Brain

Surprisingly little is known about the mechanisms that trigger the onset of AD (Alzheimer's disease) in sporadic forms. A number of risk factors have been identified that may shed light on the mechanisms that may trigger or facilitate the development of AD. Recently, T2DM (Type 2 diabetes mellitus) has been identified as a risk factor for AD. A common observation for both conditions is the desensitization of insulin receptors in the brain. Insulin acts as a growth factor in the brain and is neuroprotective, activates dendritic sprouting, regeneration and stem cell proliferation. The impairment of this important growth factor signal may facilitate the development of AD. Insulin as well as other growth factors have shown neuroprotective properties in preclinical and clinical trials. Several drugs have been developed to treat T2DM, which re-sensitize insulin receptors and may be of use to prevent neurodegenerative processes in the brain. In particular, the incretins GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insolinotropic polypeptide) are hormones that re-sensitize insulin signalling. Incretins also have similar growth-factor-like properties as insulin and are neuroprotective. In mouse models of AD, GLP-1 receptor agonists reduce amyloid plaque formation, reduce the inflammation response in the brain, protect neurons from oxidative stress, induce neurite outgrowth, and protect synaptic plasticity and memory formation from the detrimental effects caused by β-amyloid production and inflammation. Other growth factors such as BDNF (brain-derived neurotrophic factor), NGF (nerve growth factor) or IGF-1 (insulin-like growth factor 1) also have shown a range of neuroprotective properties in preclinical studies. These results show that these growth factors activate similar cell signalling mechanisms that are protective and regenerative, and suggest that the initial process that may trigger the cascade of neurodegenerative events in AD could be the impairment of growth factor signalling such as early insulin receptor desensitization.

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Banxia Xiexin decoction ameliorated cognition via the regulation of insulin pathways and glucose transporters in the hippocampus of APPswe/PS1dE9 mice

International Journal of Immunopathology and Pharmacology ◽

10.1177/2058738418780066 ◽

2018 ◽

Vol 32 ◽

pp. 205873841878006 ◽

Cited By ~ 3

Author(s):

Fang Chen ◽

Yingkun He ◽

Pengwen Wang ◽

Peng Wei ◽

Huili Feng ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Glucose Metabolism ◽

Transgenic Mice ◽

Cognitive Performance ◽

Insulin Signalling ◽

Glucose Transporter 1 ◽

Double Transgenic Mice ◽

Banxia Xiexin Decoction

Reduced glucose utilization and deficient energy metabolism that occur in the early stages of Alzheimer’s disease correlate with impaired cognition, and this information is evidence that Alzheimer’s disease is a metabolic disease that is associated with brain insulin/insulin-like growth factor resistance. This research aimed to investigate the effects of Banxia Xiexin decoction (BXD) on cognitive deficits in APPswe/PS1dE9 double transgenic mice and verify the hypothesis that BXD treatment improves cognitive function via improving insulin signalling, glucose metabolism and synaptic plasticity in the hippocampus of APPswe/PS1dE9 double transgenic mice. We used 3-month-old APPswe/PS1dE9 double transgenic mice as the case groups and wild-type littermates of the double transgenic mice from the same colony as the control group. Forty-five APPswe/PS1dE9 double transgenic mice were randomly divided into the model group, donepezil group and BXD group. The mice in the control and model groups were administered 0.5% carboxymethyl cellulose orally. The Morris water maze and step-down test were conducted to evaluate the cognitive performance of APPswe/PS1dE9 double transgenic mice after BXD treatment. Ultrastructure of synapses was observed in the hippocampal CA1 area. Proteins involved in insulin signalling pathways and glucose transports in the hippocampus were assessed through immunohistochemical staining and western blot. After 3 months intervention, we found that BXD treatment improved cognitive performance and the synaptic quantity and ultrastructure, restored insulin signalling and increased the expression of glucose transporter 1 (GLUT1) and GLUT3 levels. These findings suggest that the beneficial effect of BXD on cognition may be due to the improvement of insulin signalling, glucose metabolism and synaptic plasticity.

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Pharmacological Interventions to Attenuate Alzheimer’s Disease Progression: The Story So Far

Current Alzheimer Research ◽

10.2174/1567205016666190301111120 ◽

2019 ◽

Vol 16 (3) ◽

pp. 261-277 ◽

Cited By ~ 12

Author(s):

Firas H. Bazzari ◽

Dalaal M. Abdallah ◽

Hanan S. El-Abhar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Disease Progression ◽

Insulin Signalling ◽

The Elderly ◽

Comprehensive Overview ◽

Slowing Down ◽

Symptomatic Management ◽

Promising Therapeutic Approach

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia in the elderly. Up to date, the available pharmacological options for AD are limited to cholinesterase inhibitors and memantine that may only provide modest symptomatic management with no significance in slowing down the disease progression. Over the past three decades, the increased interest in and the understanding of AD major pathological hallmarks have provided an insight into the mechanisms mediating its pathogenesis, which in turn introduced a number of hypotheses and novel targets for the treatment of AD. Initially, targeting amyloid-beta and tau protein was considered the most promising therapeutic approach. However, further investigations have identified other major players, such as neuroinflammation, impaired insulin signalling and defective autophagy, that may contribute to the disease progression. While some promising drugs are currently being investigated in human studies, the majority of the previously developed medical agents have come to an end in clinical trials, as they have failed to illustrate any beneficial outcome. This review aims to discuss the different introduced approaches to alleviate AD progression; in addition, provides a comprehensive overview of the drugs in the development phase as well as their mode of action and an update of their status in clinical trials.

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