OVEREXPRESSION OF CELLULAR PRION PROTEIN (PRPC) PREVENTS COGNITIVE DYSFUNCTION AND APOPTOTIC NEURONAL CELL DEATH INDUCED BY AMYLOID-beta (AB_(1-40)) ADMINISTRATION IN MICE

摘要

The cellular priori protein (PrPc) is a neuronal-anchored glycoprotein that has been associated with several functions in the CNS such as synaptic plasticity, learning and memory and neuroprotection. There is great interest in understanding the role of PrPc in the deleterious effects induced by the central accumulation of amyloid-p (Ap) peptides, a pathological hallmark of Alzheimer's disease, but the existent results are still controversial. Here we compared the effects of a single intracerebroventricular (i.c.v.) injection of aggregated Ap1_40 peptide (400pmol/ mouse) on the spatial learning and memory performance as well as hippocampal cell death biomarkers in adult wild type (Prnp+/+), PrPc knockout (Prnp0/0) and the PrPc over-expressing Tg-20 mice. Tg-20 mice, which present a fivefold increase in PrPc expression in comparison to wild type mice, were resistant to the A beta_(1-40)-induced spatial learning and memory impairments as indicated by reduced escape latencies to find the platform and higher percentage of time spent in the correct quadrant during training and probe test sessions of the water maze task. The protection against A beta_(1-40) 40-induced cognitive impairments observed in Tg-20 mice was accompanied by a significant decrease in the hippocampal expression of the activated caspase-3 protein and Bax/Bcl-2 ratio as well as reduced hippocampal cell damage assessed by MTT and propidium iodide incorporation assays. These findings indicate that the overexpression of PrPc prevents Ap1_40-induced spatial learning and memory deficits in mice and that this response is mediated, at least in part, by the modulation of programed cell death pathways.