FIGURE 3.

The Acetylcholine Hypothesis and role of AChE Inhibition: Decreased levels of acetylcholine (ACh) contribute to cognitive decline; however, the inhibition of acetylcholinesterase (AChE) with acetylcholinesterase inhibitors (AChEIs) prevents the breakdown of ACh, thus resulting in elevated synaptic ACh levels. The increase in available ACh is associated with improved cognitive function. AChE also interacts with the enzyme presenilin-1 PS-1, which plays a crucial role in Aβ production including the regulation of γ-secretase, and its association with AChE underscores a significant cholinergic-amyloid link in the pathophysiology of AD. Mutations in the PSENI gene result in the enhanced production of Aβ (Silveyra et al., 2008). It has been reported that AChE enhances both transcription and production of PS-1, decreasing γ-secretase activity and reducing the processing of APP (Campanari et al., 2014). Thus, the loss of the regulation of PS-1 by AChE and a subsequent increase in γ-secretase activity will increase Aβ. This figure was created with BioRender.com.