Amyloid ß lowering and cognition enhancing effects of ghrelin receptor analog [D-Lys (3)] GHRP-6 in rat model of obesity.

Obesity arising due to the dietary and life style changes is fast reaching epidemic proportions all over the world. There is increasing evidence that the incidence of Alzheimer disease (AD) is significantly influenced by a cluster of metabolic diseases, including diabetes and obesity. This study was aimed to test the suitability of experimentally-induced obesity in rats as an experimental animal model of AD. We used the procedure of neonatal administration of rats with monosodium L-glutamate (MSG), which generates adult obese animals as our study design and assessed the AD-like changes by measuring amyloid ß (1-42) and acetylcholinesterase (AChE) levels in the hippocampal extracts and cognitive impairments by Barnes maze task. Further, we investigated the influence of anti-obesity substance [D-Lys (3)] GHRP-6 on blood glucose, hippocampal Aß, AChE levels and restoration of cognitive deficits. Results revealed that administration of MSG to neonatal rats exhibited increased body mass index and serum glucose levels over the controls. Measurement of markers for AD-like molecular changes i.e. amyloid ß (Aß) and AChE levels showed marked elevation in these two parameters in the hippocampus of MSG-treated rats. Assessment of cognitive abilities by Barnes maze revealed spatial disorientation characteristic of AD. Administration of ghrelin receptor analog [D-Lys (3)] GHRP-6 to obese rats resulted in significant restoration of serum cholesterol, glucose, leptin and ghrelin levels to that of control with concomitant reduction in hippocampal Aß and AChE levels. In addition, the treated animals exhibited marked improvement in Barne’s maze task. These findings suggest that MSG-induced obese rats may serve as non-transgenic animal model for AD research. Further, the results indicate the potential of [D-Lys (3)] GHRP-6 as a promising anti-Alzheimer candidate.

I32E and V36K double mutation in ß2-sheet abrogates amyloid ß peptide toxicity.

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, wherein, the accumulation of amyloid ß(Aß) peptide as cytotoxic oligomers leads to neuropathologic changes. Transgenic mice with brain Aß plaques immunizedwith aggregated Aß have reduced amyloid burden and improved cognitive functions. However, such active immunization inhumans led to a small but significant occurrence of meningoencephalitis in 6% AD volunteers due to Aß induced toxicity. Inan attempt to develop safer alternative vaccines, the design of a highly soluble peptide homologous to Aß (Aß-EK), that hasa reduced amyloidogenic potential while maintaining the major immunogenic epitopes of Aß is reported. More importantly,this homologue has been shown to be non-toxic, as this peptide failed to exert any observable effect on erythrocytes. Theresults of the present study suggests that immunization with non-toxic Aß derivative may offer a safer therapeutic approachto AD, instead of using toxic Aß fibrils.