1. SEN1500, a novel oral amyloid-β aggregation inhibitor, attenuates brain pathology in a mouse model of Alzheimer’s disease
- Author
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S. Flunkert, J. Neddens, D. Brunner, J.M. Treherne, D.I.C. Scopes, Birgit Hutter-Paier, and S. Duller
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0301 basic medicine ,Genetically modified mouse ,Pathology ,medicine.medical_specialty ,Spatial Learning ,Hippocampus ,Mice, Transgenic ,Plaque, Amyloid ,Neuropathology ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Amyloid precursor protein ,Animals ,Medicine ,Neuroinflammation ,Cerebral Cortex ,Memory Disorders ,Amyloid beta-Peptides ,Aniline Compounds ,Microglia ,biology ,business.industry ,General Neuroscience ,P3 peptide ,Brain ,Peptide Fragments ,Mice, Inbred C57BL ,Disease Models, Animal ,Pyrimidines ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,Encephalitis ,Astrocytosis ,business ,030217 neurology & neurosurgery - Abstract
Introduction Amyloid-β (Aβ) aggregation is thought to be a major pathogenic event underlying the neuropathology of Alzheimer’s disease (AD). The development of new drugs inhibiting the Aβ aggregation process is, therefore, important. SEN1500, an orally bioavailable and CNS-penetrant Aβ aggregation inhibitor, has previously been shown to reduce spatial learning and memory deficits in an APP transgenic mouse model. To verify that the pharmacological properties of SEN1500 are not unique to this model, we investigated brain Aβ pathology, neuroinflammation, as well as memory in a different mouse model of AD expressing the human amyloid precursor protein with Swedish and London mutations (APP SL ). Materials & methods APP SL transgenic mice and non-transgenic littermates were treated with SEN1500 via food pellets from three months of age for four months. At the end of the treatment, animals were tested for memory deficits using the contextual fear conditioning test and brain tissue was analyzed for soluble and insoluble amyloid-β1-38, -40, -42, β-amyloid plaques, β-sheet plaque cores, as well as for astrocytosis and activated microglia. Results SEN1500 treatment lowered insoluble Aβ levels and β-amyloid plaque load in the brain compared with control-treated APP SL mice. Activated microglia were significantly reduced in the cortex but not the hippocampus of SEN1500-treated APP SL mice. Memory deficits of APP SL mice could not be rescued by SEN1500. Discussion SEN1500 is not only able to reduce Aβ pathology and activated microglia but also to improve learning and memory as previously shown, making SEN1500 a potential candidate for human AD treatment. This Aβ aggregation inhibitor could be a promising therapeutic agent for the disease-modifying treatment of AD.
- Published
- 2017
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