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.

Figure 1

Amyloid precursor protein (APP) mutations. (a) The APP transmembrane domain (TMD) extends from the glycine in position 700 to the lysine in position 723. The Aβ42 peptide isoform is highlighted in yellow. Depicted by arrows are the β-secretase (BACE1) cleavage site, the γ-secretase cleavage sites generating Aβ40 and Aβ42, and the ε-cleavage sites. According to the sequential cleavage model, ε-cleavage is the initiating event for the stepwise generation of Aβ peptides, which proceeds from the ε-site to the γ-cleavage sites and reflects the periodicity of the APP TMD α-helix. Amino acid exchanges causative of either familial Alzheimer's disease (FAD) or cerebral amyloid angiopathy (CAA) are shown below the peptide sequence. (b) Timeline of the discovery of APP mutations (see also [55]).

Figure 2

Tissue culture models of presenilin (PSEN) mutations. In most studies, PSEN mutants have been stably overexpressed either in permanent cells lines (left) or in PSEN1/PSEN2-/- double-knockout cell lines (middle). Due to the replacement phenomenon or the lack of endogenous wild type (WT) PSEN proteins, functional γ-secretase complexes in both of these tissue culture models contain predominantly or solely the exogenously expressed PSEN mutants. This situation is different from familial Alzheimer's disease (FAD) patients with heterozygous PSEN1 (or PSEN2) mutations that express mutant and WT PSEN1 (or PSEN2) in an equal ratio in the background of two WT PSEN2 (or PSEN1) alleles (right). CMV, cytomegalovirus.