engleski

The significance of the experimental models in Alzheimer's disease drug development

Alzheimer disease (AD) is a progressive and incurable neurodegenerative disorder, the most common cause of dementia. There is an increasing need for developing relevant animal models to facilitate translational research and preclinical drug development. Widely exploited transgenic mice AD models are based on the utilization of genetic mutations associated with familial AD. However, the vast majority of AD cases are of a sporadic origin (sAD) and unknown cause, thereby increasing the urgency of designing and characterizing a representative sAD animal model. Recent data indicates that the development of insulin resistant brain state (IRBS) found post mortem might be a possible factor underlying the cognitive and neuroptahological hallmarks of sAD. In line with that, induction of IRBS in rats by intracerebroventricular (icv) administration of streptozotocin (STZ, a compound selectively toxic to insulin producing/secreting and insulin receptor expressing cells), has been recognized as a suitable experimental approach and STZ-icv treated rats as a representative non-transgenic sAD animal model. STZ-icv model shares a numerous cognitive, neurochemical and structural similarities with sAD patients and has been exploited in a number of AD drug testing experiments. However, there has been some discordance between these preclinical drug studies and corresponding human clinical trials. Careful designing of drug interventional studies in STZ-icv animal sAD model based on our recent data on STZ-icv dose- and time-dependent pattern of pathophysiological alterations will be discussed as a tool to solve the translational issues and increase the predictive value in translating the results to humans.

Alzheimer's disease; insulin resistance; drug development; streptozotocin

nije evidentirano