Project summary:

   Alzheimer's disease (AD) is characterized by progressive degradation of memory processes, being associated with three major changes that occur in the brain: i) the formation of intra- and extracellular beta-amyloid deposits; ii) the appearance of neurofibrillary tangles and iii) the death of cholinergic neurons and a significant decrease in acetylcholine level. The identification of neuroprotective therapies for AD was dominated by the hypothesis of amyloid cascade and tau proteins. Unfortunately, both approaches have so far failed to provide an effective therapeutic strategy. The involvement of α7 and α4β2 subtypes of nicotinic receptors (nAChRs) in the pathogenesis of AD has led to the proposal of a new therapeutic approach. Immunohistochemical studies in the brains of patients with sporadic AD have shown that Aβ1-42 and α7nAChR are present in neuritic plaques and this interaction may be inhibited by α7nAChRs ligands. Nicotine, through its ability to bind to nAChRs is the ideal molecule for the development of new derivatives with therapeutic applications. The project aims to test the antiaggregating potential against Aβ1-42 of 6-hydroxy-L-nicotine (6HLN), derived from the metabolism of nicotine in the microorganism Paenarthrobacter nicotinovorans pAO1. To achieve this goal, the project activities will focus on evaluating the action of 6HLN in vitro on cell lines and in vivo on 5xFAD transgenic mice, in order to identify its therapeutic potential.

Project members: