title: Molecular consequences of amyloid precursor protein and presenilin mutations causing autosomal-dominant Alzheimer's disease.
abstract: Mutations in both the amyloid precursor protein (APP) and the presenilin (PSEN) genes cause familial Alzheimer's disease (FAD) with autosomal dominant inheritance and early onset of disease. The clinical course and neuropathology of FAD and sporadic Alzheimer's disease are highly similar, and patients with FAD constitute a unique population in which to conduct treatment and, in particular, prevention trials with novel pharmaceutical entities. It is critical, therefore, to exactly defi ne the molecular consequences of APP and PSEN FAD mutations. Both APP and PSEN mutations drive amyloidosis in FAD patients through changes in the brain metabolism of amyloid-β (Aβ) peptides that promote the formation of pathogenic aggregates. APP mutations do not seem to impair the physiological functions of APP. In contrast, it has been proposed that PSEN mutations compromise γ-secretase-dependent and -independent functions of PSEN. However, PSEN mutations have mostly been studied in model systems that do not accurately refl ect the genetic background in FAD patients. In this review, we discuss the reported cellular phenotypes of APP and PSEN mutations, the current understanding of their molecular mechanisms, the need to generate faithful models of PSEN mutations, and the potential bias of APP and PSEN mutations on therapeutic strategies that target Aβ.
authors.affiliation: Department of Neuropathology, Heinrich-Heine-University, Moorenstrasse 5, D-40225 Düsseldorf, Germany. sweggen@uni-duesseldorf.de.
authors.forename: Sascha
authors.initials: S
authors.lastname: Weggen
authors.forename: Dirk
authors.initials: D
authors.lastname: Beher