Analysis of the cholinergic system in Alzheimer’s disease: a study of toxicity and regulation of stress response in cholinergic cells

Abstract

Alzheimer’s disease, the most common cause of dementia, is a chronic neurodegenerative disorder that slowly impairs the cognitive abilities of the patient, leading to a progressive neuronal loss. The main molecular neuropathological hallmarks are the intracellular neurofibrillary tangles and the extracellular accumulation of amyloid-β peptide forming senile plaques. Among the different cell types affected, early alterations have been described in the basal forebrain cholinergic neurons, together with intraneuronal accumulation of amyloid-β peptide (Aβ) on these cells, and deficits in the cholinergic system, hence hypothesizing a possible epicenter for the onset of the disease in basal forebrain cholinergic neurons, although the mechanisms and processes involved remain unknown. This project will help to better understand those mechanisms by studying basal forebrain cholinergic neurons susceptibility to stressors. The cholinergic cell line SN56.B5.G4 and primary cultures derived from the nucleus basal of Meynert of mice will be used in the study consisting in the analysis of: i) the response of cholinergic neurons to peroxide and Aβ; ii) the role of calbindin in the protection against Aβ induced neurotoxicity; iii) the intracellular trafficking of Aβ. Together with this, studies in glucose-deprivation scenarios will be performed. Moreover, slices of mice brains at different ages will be used to evaluate the trafficking of the intracellular Aβ, in order to describe possible mechanisms of Aβ delivery to other brains regions such as cortical areas or hippocampus. Altogether, this project aim’s is to provide useful information to better understand the onset and progression of the disease and to describe possible targets to prevent it.