Rhein-Huprine Derivatives Reduce Cognitive Impairment, Synaptic Failure and Amyloid Pathology in AβPPswe/PS-1 Mice of Different Ages

Author(s): Felipe G. Serrano, Cheril Tapia-Rojas, Francisco J. Carvajal, Pedro Cisternas, Elisabet Viayna, Irene Sola, Diego Munoz-Torrero, Nibaldo C. Inestrosa.

Journal Name: Current Alzheimer Research

Volume 13 , Issue 9 , 2016

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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.

Keywords: AD animals model, amyloid β peptide, tau, Rhein-huprine hybrids, LTP, memory.

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Article Details

VOLUME: 13
ISSUE: 9
Year: 2016
Page: [1017 - 1029]
Pages: 13
DOI: 10.2174/1567205012666151027141542
Price: $58

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