Mechanisms linking brain insulin resistance to Alzheimer's disease

• Main Authors: Maria Niures P.S. Matioli, Ricardo Nitrini
• Format: Article
• Language: English
• Published: Associação Neurologia Cognitiva e do Comportamento
• Series: Dementia & Neuropsychologia
• Subjects: Alzheimer's disease; diabetes mellitus; insulin resistance; neurodegeneration; mechanisms
• Online Access: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1980-57642015000200096&lng=en&tlng=en

Several studies have indicated that Diabetes Mellitus (DM) can increase the risk of developing Alzheimer's disease (AD). This review briefly describes current concepts in mechanisms linking DM and insulin resistance/deficiency to AD. Insulin/insulin-like growth factor (IGF) resistance can contribute to neurodegeneration by several mechanisms which involve: energy and metabolism deficits, impairment of Glucose transporter-4 function, oxidative and endoplasmic reticulum stress, mitochondrial dysfunction, accumulation of AGEs, ROS and RNS with increased production of neuro-inflammation and activation of pro-apoptosis cascade. Impairment in insulin receptor function and increased expression and activation of insulin-degrading enzyme (IDE) have also been described. These processes compromise neuronal and glial function, with a reduction in neurotransmitter homeostasis. Insulin/IGF resistance causes the accumulation of AβPP-Aβ oligomeric fibrils or insoluble larger aggregated fibrils in the form of plaques that are neurotoxic. Additionally, there is production and accumulation of hyper-phosphorylated insoluble fibrillar tau which can exacerbate cytoskeletal collapse and synaptic disconnection.