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Abnormalitiesin insulin metabolism, characteristic of T2DM, are among the major factorsthought to mechanistically influence the onset of AD. These abnormalitiesare thought to play a role in AD via their influence on the synthesis anddegradation of Aβ and as aconsequence of the cascade of neuronal alterations resulting from the effectsof danger-alarm signals from oligomeric amyloid species. Additionally, recentstudies have indicated that certain signal transduction pathways downstream ofthe InsR may also promote the generation of Aβ peptides by modulating the cleavage of the parent Aβ precursor protein AβPP at the γ-secretase site, a cleavage site necessary for Aβ amyloidogenicity. Glucose homeostasisis critical for energy generation, neuronal maintenance, neurogenesis, neurotransmitterregulation, cell survival and synaptic plasticity. It also plays a key rolein cognitive function. In an insulin resistance condition, there is a reducedsensitivity to insulin resulting in hyperinsulinemia; this condition persistsfor several years before becoming full blown diabetes. Toxic levels ofinsulin negatively influence neuronal function and survival, and elevation ofperipheral insulin concentration acutely increases its cerebrospinal fluid CSF concentration. Peripheral hyperinsulinemia correlates with an abnormal removal of the amyloid beta peptide Aβ and an increase of tau hyperphosphorylationas a result of augmented cdk5 and GSK3β activities. This leads to cellular cascades that trigger a neurodegenerativephenotype and decline in cognitive function. Chronic peripheralhyperinsulinemia results in a reduction of insulin transport across the BBBand reduced insulin signaling in brain, altering all of insulin’s actions,including its anti-apoptotic effect. However, the increase in brain insulinlevels resulting from its peripheral administration at optimal doses hasshown a cognition enhancing effect on patient with AD.

KEYWORDS

Insulin Resistance; B-Amyloid; Oxidative Stress; Brain Inflammation

Cite this paper

Ghareeb, D. , Mohamed, S. and El-Sayed, M. 2013 The interrelationship between insulin resistane and Alzheimer development. Journal of Biomedical Science and Engineering, 6, 754-773. doi: 10.4236-jbise.2013.67093.





Author: Doaa A. Ghareeb, Shimaa Mohamed, Mohamed El-Sayed

Source: http://www.scirp.org/



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