The study supports the hypothesis that an impaired control of glycogen synthase kinase-3beta activity by insulin receptor-mediated signalling plays a role in the pathogenesis of AD, facilitating tau protein phosphorylation and neurofibrillary tangle formation.
Furthermore, postmortem analyses of brains from patients with AD revealed a markedly downregulated expression of insulin receptor (IR), IGF-1 receptor (IGF-1R), insulin receptor substrate (IRS)-1 and IRS-2, and these changes progress with severity of neurodegeneration.
Combination of Insulin with a GLP1 Agonist Is Associated with Better Memory and Normal Expression of Insulin Receptor Pathway Genes in a Mouse Model of Alzheimer's Disease.
Insulin and the IR are also present in the brain, and since there is evidence that neuronal insulin signaling regulates synaptic plasticity and that it is impaired in disease, this pathway might be the key to protection or reversal of symptoms, especially in Alzheimer's disease.
Since IR expression is diminished in type-2 diabetes as well as in Alzheimer's disease (AD) patients, these data may provide a mechanistic link between insulin resistance, impaired synaptic transmission and cognitive decline in humans with metabolic disorders.
Reported evidence shows that vascular risk factors are associated with AD, particularly in the development of protein aggregation, inflammation, oxidative stress, neuronal dysfunction, and disturbances in signaling pathways, with insulin receptor signaling being a common alteration between MetS and AD.
Rat brain glucose transporter-2, insulin receptor and glial expression are acute targets of intracerebroventricular streptozotocin: risk factors for sporadic Alzheimer's disease?
Here, we show that microRNA 7 (miR-7), an abundant microRNA in the brain, targets insulin receptor (INSR), insulin receptor substrate 2 (IRS-2), and insulin-degrading enzyme (IDE), key regulators of insulin homeostatic functions in the central nervous system (CNS) and the pathology of AD.
However, when the samples were analyzed separately according to the region of the brain, there was a significant upregulation of INSR expression in the hippocampus and the entorhinal cortex in the AD patient group.
Disturbances of brain glucose uptake, glucose tolerance, glucose utilization and of the insulin/insulin receptor signaling cascade are thought to be key features of the pathophysiology of AD.
Defective insulin receptor signalings are associated with the dementia in normal aging and patients with age-related neurodegenerative diseases (e.g., Alzheimer's disease); the cognitive impairment can be reversed with systemic administration of insulin in the euglycemic condition.
Regulation of Aβ production by glucose and insulin and effects of Aβ on the insulin receptor pathway suggest similar cellular mechanisms may exist between neuronal dysfunction in Alzheimer disease and adipose dysfunction in type 2 diabetes.
Following these discoveries, evidence of decreased brain insulin receptor number and function was reported in both clinical samples and animal models of aging and Alzheimer's disease, setting the stage for the hypothesis that neuronal insulin resistance may underlie memory loss in these conditions.
Parahippocampal gyrus expression of endothelial and insulin receptor signaling pathway genes is modulated by Alzheimer's disease and normalized by treatment with anti-diabetic agents.
To define the role of IR in this context, we crossed neuron-specific IR knockout mice (nIR(-/-)) with Tg2576 mice, a well-established mouse model of an AD-like pathology.
The cross-talk between NGF and insulin pathways downstream the insulin receptor suggests novel potential therapeutic targets to slow cognitive decline in AD and diabetes-related brain insulin resistance.
Alzheimer's disease (AD) is associated with reduced insulin level and impairment of insulin receptor (IR) signaling in the brain, which correlates to amyloid pathology, neuroinflammation, and synaptic neurotoxicity.
Brain protein O-GlcNAcylation is diminished in Alzheimer's disease (AD), and OGT targets include proteins of the insulin-signaling pathway (e.g., insulin receptor susbtrate-1, IRS-1).
Alzheimer's disease (AD) is associated with progressive impairments in brain insulin, insulin-like growth factor (IGF), and insulin receptor substrate (IRS) signaling through Akt pathways that regulate neuronal growth, survival, metabolism, and plasticity.The intracerebral streptozotocin (i.c.