Cellular stress reactions as putative cholinergic links in Alzheimer's disease

Alzheimer's disease involves normal cellular aging and chronic cellular stress events, leading to interrelated changes in gene expression and subsequent neurodegeneration. Premature death of cholinergic neurons and the formation of amyloid fibrils separately initiated the cholinergic and amyloid hypotheses of Alzheimer's disease. Here, we present evidence to the fact that these two distinct phenomena both associate with specific changes in acetylcholinesterase (AChE) gene expression within cholinergic neurons. For example, calcium misregulation promotes aberrant transcription and pro-apoptotic events, as well as AChE-induced modifications in cellular signal cascades. These reciprocally intercept with AChE regulation at the Endoplasmic Reticulum, modifying AChE gene expression, folding and signaling. Altered AChE properties may reflect changes in the enzymatic and/or non-enzymatic features of the multiple AChE splice variants. Under chronic cellular stress, aberrant AChE regulation may thus facilitate apoptotic pathways, promoting plaque formation, cognitive impairments and degeneration of cholinergic nerve cells.