Journal
CURRENT ALZHEIMER RESEARCH
Volume 13, Issue 9, Pages 1017-1029Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1567205012666151027141542
Keywords
AD animals model; amyloid beta peptide; tau; Rhein-huprine hybrids; LTP; memory
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Funding
- Basal Centre for Excellence in Science and Technology [PFB 12/2007]
- FONDECYT [1120156]
- Ministerio de Ciencia e Innovacion and Generalitat de Catalunya (GC) [CTQ2011-22433, 2009SGR1396]
- CONICYT
- VRI of the Catholic University of Chile
- GC
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Alzheimer's disease (AD) is a neurodegenerative disorder in which the amyloid-beta (A beta) 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 A beta 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 A beta PPswe/PS-1 Alzheimer's model, including a reduction in the A beta 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.
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