Title:Rhein-Huprine Derivatives Reduce Cognitive Impairment, Synaptic Failure and Amyloid Pathology in AβPPswe/PS-1 Mice of Different Ages
Volume: 13
Issue: 9
Author(s): Felipe G. Serrano, Cheril Tapia-Rojas, Francisco J. Carvajal, Pedro Cisternas, Elisabet Viayna, Irene Sola, Diego Munoz-Torrero and Nibaldo C. Inestrosa
Affiliation:
Keywords:
AD animals model, amyloid β peptide, tau, Rhein-huprine hybrids, LTP, memory.
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.
