P4-302: Lipoprotein-induced chromosome missegregation in vitro and in vivo: Implications for cardiovascular and Alzheimer's disease

Abstract

Alzheimer’s disease (AD) by 50-100% as well. The effect seems largely independent of other, so-called vascular risk factors. Methods: Literature search has been conducted to unravel the mechanisms mediating the association between DM and AD. Results: Putative hypotheses explaining this association comprise chronic brain hypoperfusion due to macroand microangiopathy, the toxic effects of hyperglycaemia itself (damage to the blood-brain barrier), and the mediating role of insulin. Brain has for long been considered an insulin-independent organ; the discovery of insulin and its receptors in the central nervous system falsified this theory. Physiologic concentrations of insulin exert a beneficial effect on cognition. On the other hand, the risk of AD is significantly increased by the state of central (brain) hypoinsulinaemia, even in people not suffering from DM. Brain insulin deficiency can be secondary to either too low a concentration of insulin in the periphery or on the contrary the state of peripheral hyperinsulinaemia, usually as a result of insulin resistance, a typical phenomenon in DM. Several mechanisms mediate between the state of central hypoinsulinaemia and the acceleration of Alzheimer pathology generation: decline of glucose utilization, particularly in the hippocampus and enthorinal cortex; increased oxidative stress associated with the synthesis of advanced glycation endproducts (AGE); increased tau protein phosphorylation and neurofibrillary tangle formation; increased aggregation of beta-amyloid protein secondary to the insulin-degrading enzyme (IDE) inhibition. Therapeutic strategies targeted at restoring the balance in insulin metabolism in AD applying nasal insulin or using thiazolidinedions are currently in the phase of clinical trials. Conclusions: The role of central insulin disturbances in AD etiologty seems underestimated. Insulin deficiency in the brain is involved in multiple mechanisms associated with AD development and progression.