1. Rhein-Huprine Derivatives Reduce Cognitive Impairment, Synaptic Failure and Amyloid Pathology in AβPPswe/PS-1 Mice of Different Ages.
- Author
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Serrano FG, Tapia-Rojas C, Carvajal FJ, Cisternas P, Viayna E, Sola I, Munoz-Torrero D, and Inestrosa NC
- Subjects
- Aging drug effects, Aging metabolism, Aging pathology, Alzheimer Disease metabolism, Alzheimer Disease pathology, Alzheimer Disease psychology, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor metabolism, Animals, Cognitive Dysfunction drug therapy, Cognitive Dysfunction metabolism, Cognitive Dysfunction pathology, Disease Models, Animal, Humans, Inflammation drug therapy, Inflammation metabolism, Inflammation pathology, Long-Term Potentiation drug effects, Long-Term Potentiation physiology, Mice, Transgenic, Peptide Fragments metabolism, Phosphorylation drug effects, Plaque, Amyloid drug therapy, Plaque, Amyloid metabolism, Plaque, Amyloid pathology, Presenilin-1 genetics, Presenilin-1 metabolism, Synapses drug effects, Synapses metabolism, Synapses pathology, tau Proteins metabolism, Alzheimer Disease drug therapy, Aminoquinolines pharmacology, Anthraquinones pharmacology, Neuroprotective Agents pharmacology, Nootropic Agents pharmacology
- Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder in which the amyloid-β (Aβ) peptide plays a key role in synaptic impairment and memory decline associated with neuronal dysfunction and intra-neuronal accumulation of hyperphosphorylated tau protein. Two novel enantiopure rhein-huprine hybrids ((+)-1 and (-)-1) exhibit potent inhibitory effects against human acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), BACE-1 and both Aβ and tau antiaggregation activity in vitro and reduction on the amyloid precursor protein (APP) processing in vivo. Interestingly, in this work, we observed beneficial effects with both (+)- and (-)-1 in the reversion of the neuropathology presented in the AβPPswe/PS-1 Alzheimer´s model, including a reduction in the Aβ levels, tau phosphorylation and memory impairment with both treatments. Also, in young transgenic mice that present early symptoms of synaptic failure and memory loss, we found a protection of cognitive functions, including long-term potentiation (LTP) and a reduction of the neuro-inflammation by both (+)- and (-)-1. Furthermore, animals with an advanced disease (11month-old) present an exacerbate neurodegeneration that is reversed only with the dextrorotatory enantiomer. These studies indicated that rhein-huprine derivatives with multiple properties might have interesting therapeutic potential for AD.
- Published
- 2016
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