title: Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease.
abstract: Presenilin mutations are the main cause of familial Alzheimer disease. From a genetic point of view, these mutations seem to result in a gain of toxic function; however, biochemically, they result in a partial loss of function in the gamma-secretase complex, which affects several downstream signalling pathways. Consequently, the current genetic terminology is misleading. In fact, the available data indicate that several clinical presenilin mutations also lead to a decrease in amyloid precursor protein-derived amyloid beta-peptide generation, further implying that presenilin mutations are indeed loss-of-function mutations. The loss of function of presenilin causes incomplete digestion of the amyloid beta-peptide and might contribute to an increased vulnerability of the brain, thereby explaining the early onset of the inherited form of Alzheimer disease. In this review, I evaluate the implications of this model for the amyloid-cascade hypothesis and for the efficacy of presenilin/gamma-secretase as a drug target.
authors.affiliation: KULeuven and Flanders Interuniversitary Institute for Biotechnology (VIB), Centre for Human Genetics, Herestraat 49, 3000 Leuven, Belgium. bart.destrooper@med.kuleuven.be
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000378:metabolism*; D053763:Presenilins / Q000235:genetics* / Q000378:metabolism*; D011487:Protein Conformation
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D053763:Presenilins; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases