The mechanisms mediating amyloidogenic effects of pregnancy and the effects of amyloid-beta on chloride cotransporter expression: Lessons learned from challenges encountered and implications for the diagnosis and etiology of Alzheimer's disease.

摘要

Symptoms of Alzheimer's disease are assumed to reflect neuropathological changes induced by the accumulation and aggregation of amyloid-beta; however, it is unclear (a) why amyloid-beta accumulates, and (b) how the subsequent alterations result in behavioural disturbances. Researchers have suggested that sex hormones and gonadotropins (among other factors) play a role in the accruement of amyloid-beta. Levels of sex hormones and gonadotropins are altered during pregnancy, and epidemiological reports indicate that pregnancy increases the likelihood of developing Alzheimer's disease. Initial studies consequently sought to determine the influence of pregnancy on plasma amyloid-beta concentrations in genetically-engineered mouse models of Alzheimer's disease and normal Long-Evans rats. Results could not be reliably interpreted, but useful technical insights were generated. In subsequent experiments, the effects of amyloid-beta on NKCC1 and KCC2 protein levels -- both of which mediate the efficacy of the GABAA receptor through maintenance of intracellular chloride concentrations -- were assessed in mouse brain. Dysregulation of excitatory and inhibitory activity in neural networks has previously been cited as an explanation of behavioural changes characteristic of Alzheimer's disease, and this claim is partially supported by data presented in this report. Taken together, the studies described in this document represent a step towards a comprehensive understanding of Alzheimer's disease etiology, complimenting the efforts of other researchers in the field who labour to develop and disseminate effective preventative strategies.