Cholinergic degeneration in early stages of Alzheimer’s disease: Loss of cholinergic phenotype or loss of cells?

Abstract

Aging-associated neurodegenerative diseases, such as Alzheimer’s disease, represent a challenge for modern medicine and neuroscience. It is considered that any disease is related to degeneration of specific neuronal populations. However, it is not clear what factors initiate this specific degeneration and at which stage therapeutic interventions may still reverse neurodegenerative process and rescue functional capacities of neurons. Here we review data showing that the early stages of Alzheimer’s disease are rather associated with a loss of cholinergic neuron phenotype in the forebrain than with neuronal death in this brain region. This is manifested in specific disappearance of choline acetyltransferase (ChAT), the key enzyme of acetylcholine synthesis, in these neurons. We hypothesize that this loss of cholinergic phenotype may be related to impairments in ChAT protein synthesis rather than in ChAT gene expression. Other potential mechanisms resulting in the loss of cholinergic phenotype are discussed.