The cholinotrophic system in Down syndrome

Cholinergic basal forebrain (CBF) projection neurons within the nucleus basalis and striatal cholinergic interneurons degenerate in individuals with Down syndrome (DS). However, the neuropathobiology of these diverse cholinergic phenotypes remains underinvestigated. This review summarizes the alterations of cholinergic, neurotrophic survival and cell death factors as well as tau pathology and amyloidopathy, and their effects upon these cell types in DS. In trisomy, the developing cholinergic system remains stable, whereas the neurotrophic receptors are compromised between control and DS cases. Both cholinergic neuronal phenotypes display severe cellular degeneration in both adult and the aged people with DS. Although developing cholinergic striatal neurons display a similar morphology between phenotypes, cholinergic striatal neurons appear dystrophic in adults with DS. Both cholinergic cell types display tau tangle pathology in elders with DS. Novel findings suggest that alterations in plasma and cerebral spinal fluid levels of proNGF, NGF metabolites, and select classes of neuronal genes are potential biomarkers to distinguish nondemented from demented people with DS. Compounds that target cholinergic pathways, TrkA agonists, p75^NTR/proNGF small molecular antagonists, NGF metabolites, and select gene ontology classes are potential targets to slow degeneration of the CBF memory connectome in DS with translation to AD.