INSULIN RESISTANT BRAIN STATE AND ALZHEIMER’S DISEASE

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Alzheimer’s disease is the most common form of dementia among older adults. In spite of indistinguishable clinical dementia symptoms, there two types of origin-based Alzheimer’s disease. In a small proportion (familial early-onset Alzheimer’s disease), the disease is caused by missense mutations in three genes, resulting in permanent generation of APP derivative Aβ which aggregates forming amyloid and plaques, while in the great majority of people (late-onset Alzheimer’s disease), it is sporadic in origin with old age as main risk factor, where Aβ has not been proven to be necessary for the generation and development of the disease (47). Among other more or less known neurochemical alterations in the brain that are beyond the scope of this review, growing evidence has identified a potential association among Alzheimer’s disease, glucose metabolism, and insulin activity (47). Patients with Alzheimer’s disease may have decreased cerebrospinal fluid levels and decreased cerebrospinal fluid to plasma insulin ratio related to impaired transport of insulin across the BBB (21), but neuronal insulin signal transduction in this disease has been in the focus of the current research. In contrast to the more localised abnormalities in the early-onset type, the late-onset type of Alzheimer’s disease is associated with glucose utilization abnormalities distributed all over the cerebral cortex, and particularly in parietotemporal and frontal areas, in structures with both high glucose demands and high insulin sensitivity (43). Since it has become obvious that neuronal glucose metabolism is under the control of the neuronal insulin, the abnormalities in neuronal glucose metabolism in Alzheimer’s disease have been suggested to be caused at the level of insulin signal transduction (46).

The up-regulation of IR density observed in hippocampus and associated with reduced activity of IR tyrosine kinase in the brain of people with sporadic Alzheimer’s disease indicates a desensitization of the neuronal IR (21,31). Proposed mechanism of inhibition of neuronal IR in the late-onset sporadic Alzheimer’s disease is related to age-induced increase in cortisol and catecholamine levels that may compromise the phosphorylation of tyrosine residues in IR (39,47). This leads to a dysfunction of subsequent insulin signal transduction, which at the level of GSK-3 kinase (α and β subtypes) results in two main pathophysiological events. In the physiological condition, PKB/Act acts to phosphorylate GSK-3 at its serine 9 residue, thereby inactivating it. Insulin normally exerts a double-sided effect on Aβs, stimulating their neuronal release (mediated through GSK-3α kinase) and in the same time contributing to extraneuronal accumulation of Aβs by competing for insulin-degrading enzyme that degrades both insulin and Aβs (34). The net action of insulin is to increase extracellular levels of Aβs in the brain. Therefore, insulin resistance-induced disinhibition of GSK-3α function in the sporadic Alzheimer’s disease leads to increased storage of APP and Aβs in neurons which then undergo lysis to form amyloid plaques, one of the main pathological features of the Alzheimer’s disease (47). These Aβs in turn reduce the binding of insulin to its receptor and receptor autophosphorylation, which in the early-onset type of Alzheimer’s disease may be the cause of triggering the dysfunction of brain insulin signal transduction (103). Also, with the fall in extracellular APPs, its mediated functions in memory enhancement may be assumed to fail, contributing to cognitive deficits (66). On the other side, insulin resistance-induced disinhibition of GSK-3β function leads to uncontrolled hyperphosphorylation of tau-protein (47). Tau is a neuronal cytoskeletal protein that binds to microtubules and promotes tubulin polymerisation and stabilization. The binding of tau to microtubules is regulated through phosphorylation by protein kinases, including GSK-3β (47). In physiological condition, insulin inhibits GSK-3β and consequently reduces tau phosphorylation, promoting binding of tau to microtubules (44). Following brain insulin dysfunction hyperphosphorylated form of tau protein builds neurofibrillary tangles, the other important pathological feature of the Alzheimer’s disease.

This impairment of the insulin signal transduction causing insulin resistant brain state is similar to condition of systemic insulin resistance in non-neuronal tissues in type 2 diabetes mellitus, suggesting a hypothesis that sporadic Alzheimer’s disease is the brain equivalent of type 2 diabetes mellitus, in other words, a kind of “cerebral” diabetes (45). Comparable to type 2 diabetes mellitus, susceptibility genes in combination with the main risk factor aging dysregulate the function of insulin signaling cascade. In addition to insulin resistance, Alzheimer’s disease (familial and sporadic) and diabetes mellitus (type 1 and 2) share the similarity in fact that both diseases are heterogenic in origin and homogenic in clinical appearance of their respective subtypes (46). It has been proposed that whether type 2 diabetes or Alzheimer’s dementia develops as a consequence of loss of sensitivity to insulin, may depend on what target tissue, neuronal or non-neuronal, becomes resistant to it (17).