The roles of GxxxG motif and gamma-secretase components in APP processing

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. Although the pathological features of AD, including excessive amyloid deposits, neurofibrillary tangles, neuroinflammatory responses, and progressive neuronal loss, have been relatively well-characterized, the pathogenic mechanisms underlying neurodegeneration and cognitive decline in AD remain unclear. Recent findings suggest that GxxxG glycine zipper motifs in amyloid-β precursor protein (APP) and Aβ peptide play critical roles in APP dimerization as well as Aβ production and fibrillogenesis. Given the fact that the glycine zipper motif is also found in α-synuclein and prion protein, already implicated in other neurodegenerative diseases, further understanding of this motif might provide novel therapeutic targets for protein misfolding disorders. Another research area of growing interest is γ-secretase. Although the process of intramembranous endoproteolysis was initially believed to be biochemically unfeasible to happen due to the hydrophobic environment of membranes, subsequent studies convincingly demonstrated that regulated intramembrane proteolysis does occur and it plays a critical role in cellular signaling and inflammatory response. Recent studies have identified more γ-secretase substrates and provided conflicting findings on the roles of γ-secretase components. Additional investigations into γ-secretase function may enhance our understanding of AD etiology and lead to the development of safer and more effective therapeutics.