PET Imaging of Epigenetic Influences on Alzheimer’s Disease

Figure 2

Wnt signaling and its relation to histone-regulated gene expression. In normal circumstances, when Wnt binds to its receptor, Frizzled, it blocks the degradation of cytosolic β-catenin, a transcription factor that then accumulates, translocates into the nucleus, and turns on transcription. LRP (low-density lipoprotein receptor-related protein) promotes Wnt-ligand binding to Frizzled. Dishevelled is a cytosolic protein associated with the tail of Frizzled. When AICD (amyloid precursor protein intracellular domain) is present, it inhibits Wnt signaling. The tumor suppressor protein APC (adenomatous polyposis coli) is then bound to the Axin protein, as well as to the kinase GSK3β (glycogen synthase kinase 3β), which triggers the phosphorylation of β-catenin that, in turn, triggers ubiquitination and degradation of β-catenin in the proteasome. The APC-Axin-GSK3β complex also phosphorylates AICD which translocates into the nucleus through a NPC (nuclear pore complex). Relevant to Alzheimer’s disease, AICD binds to Fe65 (an Aβ-binding protein) which facilitates its binding to Tip60 (a type of HAT, histone acetyltransferase). This complex can then alter expression of the NEP (neprilysin) gene, which causes neuronal degradation.