Beneficial effects of a neurotrophic peptidergic mixture persist for a prolonged period following treatment interruption in a transgenic model of Alzheimer’s disease

摘要

Neurodegenerative disorders such as Alzheimer’s disease (AD) are characterized by the loss of neurotrophic factors and experimental therapeutical approaches to AD have investigated the efficacy of replacing or augmenting neurotrophic factor activity.Cerebrolysin™, a peptide mixture with neurotrophic-like effects, has been shown to improve cognition in patients with AD and to reduce synaptic and behavioral deficits in transgenic (tg) mice over expressing the amyloid precursor protein (APP). However it is unclear how long lasting the beneficial effects of Cerebrolysin™ are and whether or not behavioral and neuropathological alterations will reappear following treatment interruption. The objective of the present study was to investigate the consequences of interrupting Cerebrolysin™ treatment (“wash-out” effect) 3 and 6 months after the completion of a 3-month treatment period in APP tg mice.We demonstrate that in APP tg mice, Cerebrolysin™-induced amelioration of memory deficits in the water maze and reduction of neurodegenerative pathology persist for 3 months after treatment interruption, however these effects dissipate 6 months following treatment termination. Immunohistochemical analysis demonstrated that the decrease in neocortical and hippocampal amyloid plaque load observed in Cerebrolysin™ treated APP tg mice immediately following treatment was no longer apparent at 3 months after treatment interruption indicating that the beneficial effects of Cerebrolysin™ at this time point were independent of its effect on amyloid-beta deposition.In conclusion the results demonstrate that effects of Cerebrolysin™ persist for a significant period of time following treatment termination and suggest that this prolonged effect may involve the neurotrophic factor-like activity of Cerebrolysin™.