@article{MRA, author = {Michael Wolfe}, title = { Beyond the Amyloid Hypothesis: Proteolytic Dysfunction in Familial Alzheimer's Disease}, journal = {Medical Research Archives}, volume = {10}, number = {8}, year = {2022}, keywords = {}, abstract = {For over 30 years, the amyloid hypothesis of Alzheimer’s disease has dominated this field of biomedical investigation. The hypothesis posits that aggregation of the amyloid β-peptide (Aβ) in the brain triggers a cascade of events that ultimately lead to neurodegeneration and cognitive decline. Early genetic and biochemical evidence supported a critical role of Aβ, particularly the 42-residue form Aβ42: Dominant missense mutations in the substrate (amyloid precursor protein, APP) and enzyme (γ-secretase) that produce Aβ cause early-onset familial Alzheimer’s disease (FAD). Nevertheless, serious gaps remain in understanding pathogenic pathways, and despite intense efforts over many years, effective agents for Alzheimer’s disease have been elusive. Here I discuss recent efforts to elucidate precisely how FAD mutations alter the complex proteolytic processing of APP substrate by γ-secretase, with results suggesting pathogenic triggers other than Aβ42.Key words: amyloid β-peptide, presenilin, γ-secretase, proteolysis}, issn = {2375-1924}, doi = {10.18103/mra.v10i8.3013}, url = {https://esmed.org/MRA/mra/article/view/3013} }