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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging / drug effects
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Aging / metabolism
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Aging / pathology
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Alzheimer Disease / psychology
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Aminoquinolines / pharmacology*
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism
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Animals
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Anthraquinones / pharmacology*
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Cognitive Dysfunction / drug therapy
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Cognitive Dysfunction / metabolism
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Cognitive Dysfunction / pathology
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Disease Models, Animal
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Humans
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Inflammation / drug therapy
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Inflammation / metabolism
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Inflammation / pathology
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Long-Term Potentiation / drug effects
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Long-Term Potentiation / physiology
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Mice, Transgenic
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Neuroprotective Agents / pharmacology*
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Nootropic Agents / pharmacology*
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Peptide Fragments / metabolism
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Phosphorylation / drug effects
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Plaque, Amyloid / drug therapy
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Plaque, Amyloid / metabolism
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Plaque, Amyloid / pathology
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Presenilin-1 / genetics
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Presenilin-1 / metabolism
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Synapses / drug effects
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Synapses / metabolism
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Synapses / pathology
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tau Proteins / metabolism
Substances
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APP protein, human
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Aminoquinolines
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Anthraquinones
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Mapt protein, mouse
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Neuroprotective Agents
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Nootropic Agents
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PSEN1 protein, human
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Peptide Fragments
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Presenilin-1
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amyloid beta-protein (1-42)
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tau Proteins