Choline metabolism as a basis for the selective vulnerability of cholinergic neurons

The unique propensity of cholinergic neurons to use choline for two purposes — ACh and membrane phosphatidylcholine synthesis — may contribute to their selective vulnerability in Alzheimer's disease and other cholinergic neurodegenerative disorders. When physiologically active, the neurons use free choline taken from the ‘reservoir’ in membrane phosphatidylcholine to synthesize ACh; this can lead to an actual decrease in the quantity of membrane per cell. Alzheimer's disease (but not Down's syndrome, or other neurodegenerative disorders) is associated with characteristic neurochemical lesions involving choline and ethanolamine: brain levels of these compounds are diminished, while those of glycerophosphocholine and glycerophosphoethanolamine (breakdown products of their respective membrane phosphatides) are increased, both in cholinergic and noncholinergic brain regions. Perhaps this metabolic disturbance and the tendency of cholinergic neurons to ‘export’ choline — in the form of ACh — underlie the selective vulnerability of the neurons. Resulting changes in membrane composition could abnormally expose intramembraneous proteins such as amyloid precursor protein to proteases.