ABSTRACT
We have previously characterized a number of small molecule organic compounds that prevent the aggregation of the β-amyloid peptide and its neurotoxicity in hippocampal neuronal cultures. We have now evaluated the effects of such compounds on amyloid precursor protein (APP) accumulation in the CTb immortalized cell line derived from the cerebral cortex of a trisomy 16 mouse, an animal model of Down's syndrome. Compared to a non-trisomic cortical cell line (CNh), CTb cells overexpress APP and exhibit slightly elevated resting intracellular Ca2+ levéis ([Ca2+]¡). Here, we show that the compounds 2,4-dinitrophenol, 3-nitrophenol and 4-anisidine decreased intracellular accumulation of APP in CTb cells. Those compounds were non-toxic to the cells, and slightly increased the basal [Ca2+]¡. Results indícate that the compounds tested can be leads for the development of drugs to decrease intracellular vesicular accumulation of APP in trisomic cells.
Subject(s)
Animals , Mice , Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/antagonists & inhibitors , Aniline Compounds/pharmacology , Down Syndrome/metabolism , Nitrophenols/pharmacology , /pharmacology , Amyloid beta-Protein Precursor/metabolism , Cell Line , Cerebral Cortex/cytology , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Disease Models, AnimalABSTRACT
The biological mechanisms underlying the neuropathology of Alzheimer's disease (AD) are complex, as several factors likely contribute to the development of the disease. Therefore, it is not surprising that a number of different possible therapeutic approaches addressing distinct aspects of this disease are currently being investigated. Among these are ways to prevent amyloid aggregation and/or deposition, to prevent neuronal degeneration, and to increase brain neurotransmitter levels. Here, we discuss possible roles of endogenous modulators of Abeta aggregation in the physiopathology of AD and some of the strategies currently under consideration to interfere with brain levels of beta-amyloid, its aggregation and neurotoxicity
Subject(s)
Humans , Alzheimer Disease , Amyloid beta-Peptides , Peptide Fragments , Alzheimer Disease , Amyloid beta-Peptides , Peptide FragmentsABSTRACT
The cells of blood vessel walls and the external surface of all blood cells have an ecto-ATPase which hydrolyzes ATP to ADP and also ADP to AMP. This enzyme has also been called apyrase or ATP-diphosphohydrolase. The enzyme hydrolyzes a broad range of tri-and diphosphate nucleosides such as UTP and UDP, GTP and GDP in additon to the adenine nucleotides and because of that it has also been called a nucleoside triphosphate hydrolase. The possible physiological roles for this ecto-ATPase involve the control of vascular tone by modulation of the levels of ATP and ADP binding to purino-receptors of the vasculature, the modulation of thrombogenesis by controlling the extracellular level of ADP which is known to activate platelet aggregation, and the protection from cytolytic effects of extracellular ATP. An ATP-diphosphohydrolase activity has been characterized on the external surface of Schistosoma mansoni, a parasite that lives in the circulation of the human host, and on the outer surface of Entamoeba histolytica, a parasite that may enter the circulation of the host through ulceration in the intestinal mucosa. The endoparasite Toxoplasma gondii also exhibits a nucleoside triphosphate hydrolase of high activity, although in this case the ecto-localization is still not documented. We raise the possibility that the endoparasites have evolved in a way to possibly mimic some of the conditions on the surface of cells normally present in the host circulation, thus escaping hemostatic defense responses of the host which require extracellular ADP or ATP.