The Brain Cholinergic System in Neurodegenerative Diseases

The neurodegenerative diseases are characterized by a progressive process of neuronal and myelin breakdown resulting in changes in the morphology and function of neurons and their death. The damage and death of the neurons is associated with an inflammatory response which involves an extensive glia activation and, through the release of inflammatory products, contributes to the neurodegenerative process. The neurodegeneration may spread throughout the brain or affect prevalently specific types of neurons such as the cholinergic neurons. Aims of this review are: 1) to describe which cholinergic nuclei degenerate in different neurodegenerative diseases, namely Alzheimer’s disease, Parkinson’s disease, Lewy Bodies dementia, atypical Parkinsonian diseases and alcoholic dementia; 2) to discuss the mechanisms responsible for the degeneration of the cholinergic neurons; 3) to summarize the functional consequences of the cholinergic denervation. A feature of Alzheimer’s disease is the loss of the forebrain cholinergic neurons leading to a cortical cholinergic denervation. A similar loss is found in Alzheimer’s disease with Lewy bodies, Parkinson disease with dementia, together with the degeneration of dopaminergic neurons, in Lewy bodies dementia and alcoholic dementia. In Lewy bodies dementia and in multiple system atrophy a loss of cholinergic neurons has been also detected in the pedunculopontine and laterodorsal tegmental nuclei, which are spared in Alzheimer’s disease and results in a cholinergic denervation of the thalamus. The degeneration of the forebrain cholinergic neurons expressing NGF receptors is attributed to a dysfunction of NGF metabolism leading to a loss of its trophic action on which those neurons depend. Whereas the direct and indirect role of β amyloid in NGF metabolism disruption has been clearly envisaged, the mechanisms through which tau fibrils, synuclein and ethanol exert their toxic effects on the cholinergic neurons are multiple and still matter of investigations. Finally, much evidence indicate that the loss of forebrain cholinergic neurons is largely responsible for the cognitive deficits of dementias.