naltrindole and Alzheimer-Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the AβPP/PS1 transgenic mouse model is a commonly used experimental model to mimic the pathological and cognitive impairments in AD. As a classic method to evaluate spatial learning and memory, the Morris water maze is widely applied to study the cognitive deficits in rodent AD models. However, the assay procedure is relatively complicated and requires a properly equipped environment. The novel object recognition test is a relatively simple and straightforward method to test working memory in rodents. However, whether the latter can be used as a common tool for evaluating the therapeutic effects of drugs in the AβPP/PS1 transgenic AD mouse model remains unclear. In the present study, we assessed the cognitive impairment of AβPP/PS1 AD mice with the novel object recognition test. In parallel, Morris water maze was performed and compared with the novel object recognition study. Both assays worked equally well in evaluating the cognitive defect of AβPP/PS1 mice. Furthermore, we drew similar conclusions from the novel object recognition assay as from the Morris water maze in assessing the therapeutic effects of two previously reported compounds, donepezil and naltrindole, on AD. We found the novel object recognition to be a facile assay with almost no stress to mice and think it could be used as an ideal primary screening assay to evaluate drug effects on AβPP/PS1 AD model.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Donepezil; Drug Evaluation, Preclinical; Female; Humans; Indans; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Naltrexone; Pattern Recognition, Visual; Piperidines; Presenilin-1; Random Allocation

Dysregulation of beta-site APP-cleaving enzyme (BACE) and/or gamma-secretase leads to anomalous production of amyloid-beta peptide (Abeta) and contributes to the etiology of Alzheimer's disease (AD). Since these secretases mediate proteolytic processing of numerous proteins, little success has been achieved to treat AD by secretase inhibitors because of inevitable undesired side effects. Thus, it is of importance to unravel the regulatory mechanisms of these secretases. Here, we show that delta-opioid receptor (DOR) promotes the processing of Abeta precursor protein (APP) by BACE1 and gamma-secretase, but not that of Notch, N-cadherin or APLP. Further investigation reveals that DOR forms a complex with BACE1 and gamma-secretase, and activation of DOR mediates the co-endocytic sorting of the secretases/receptor complex for APP endoproteolysis. Dysfunction of the receptor retards the endocytosis of BACE1 and gamma-secretase and thus the production of Abeta. Consistently, knockdown or antagonization of DOR reduces secretase activities and ameliorates Abeta pathology and Abeta-dependent behavioral deficits, but does not affect the processing of Notch, N-cadherin or APLP in AD model mice. Our study not only uncovers a molecular mechanism for the formation of a DOR/secretase complex that regulates the specificity of secretase for Abeta production but also suggests that intervention of either formation or trafficking of the GPCR/secretase complex could lead to a new strategy against AD, potentially with fewer side effects.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Carbamates; Cells, Cultured; Dipeptides; Enkephalin, Leucine-2-Alanine; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiprotein Complexes; Naltrexone; Narcotic Antagonists; Protein Transport; Receptors, G-Protein-Coupled; Receptors, Opioid, delta; Substrate Specificity; Transport Vesicles