Fig. 2.

Hypothetical model of the pathogenesis of Alzheimer’s disease driven by DNA hypomethylation events. Involvement of DNA hypomethylation in the biogenesis and processing of APP in the human brain. First, hypomethylation of the APP promoter provokes an overexpression of the APP gene, leading to greater levels of APP protein in the brain (i). Second, the hypomethylation and up-regulation of the PS1 gene induces the activity of the γ-secretase complex and stimulates the proteolytic cleavage of APP (ii), leading to the accumulation of Aβ40 and Aβ42. Note that genes encoding nicastrin (NCSTN), anterior pharynx defective 1 (APH-1), and presenilin enhancer 2 (PEN-2), three other components of the γ-secretase complex, also contain CpG islands according to http://cpgislands.usc.edu [35] and may be regulated by DNA methylation