Clinical Drug Trial Section
List of Drugs in Development for Neurodegenerative Diseases
Update June 2007Pogačić V. · Herrling P.
Corporate Research, Novartis International AG, Basel, Switzerland
Prof. Paul Herrling
Novartis International AG
CH–4002 Basel (Switzerland)
Tel. +41 61 324 7735, Fax +41 61 324 2141, E-Mail Paul.Herrling@group.novartis.com
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Background/Aims: Alzheimer’s disease (AD) is characterized by extracellular Aβ peptide deposition originating from amyloid precursor protein cleavage and intracellular neurofibrillary tangles resulting from pathological tau protein aggregation. These processes are accompanied by dramatic neuronal losses, further leading to different cognitive impairments. Neuronal death signalings involve gene expression modifications that rely on transcription factor alterations. Herein, we investigated the fate of the Sp family of transcription factors in postmortem brains from patients with AD disease and in different contexts of neuronal death. Methods/Results: By immunohistochemistry we found that the Sp3 and Sp4 levels were dramatically increased and associated with neurofibrillary tangles and pathological tau presence in neurons from the CA1 region of the hippocampus, as well as the entorhinal cortex of AD patient brains. The Sp transcription factor expression levels were further analyzed in cortical neurons in which death is induced by amyloid precursor protein signaling targeting. While the Sp1 levels remained constant, the Sp4 levels were slightly upregulated in response to the death signal. The Sp3 isoforms were rather degraded. Interestingly, when overexpressed by transfection experiments, the three Sp family members induced neuronal apoptosis, Sp3 and Sp4 being the most potent proapoptotic factors over Sp1. Conclusion: Our data evidence Sp3 and Sp4 as new hallmarks of AD in postmortem human brains and further point out that Sp proteins are potential triggers of neuronal death signaling cascades.
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