Molecular consequences of amyloid precursor protein and presenilin mutations causing autosomal-dominant Alzheimer's disease

Sascha Weggen,Dirk Beher

doi:10.1186/alzrt107

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.

Highlights

Alzheimer’s disease (AD) is the most common agerelated neurodegenerative disorder, currently affecting 20 to 30 million individuals worldwide [1]
Missense mutations that are causative of familial AD (FAD) have been identified in three genes that are essential for the generation of Aβ peptides: the amyloid precursor protein (APP) gene and two homologous genes that encode the catalytic subunit of γ-secretase, PSEN1 and PSEN2 [2,3]
Biochemical studies have shown that APP mutations either shift the generation of Aβ peptides towards the highly amyloidogenic Aβ42 isoform or enhance the aggregation propensity of the Aβ peptides

Summary

Introduction

Alzheimer’s disease (AD) is the most common agerelated neurodegenerative disorder, currently affecting 20 to 30 million individuals worldwide [1]. This was confirmed in kinetic in vitro studies using solubilized membrane preparations from heterozygous (WT/R278I) or homozygous knock-in mice, which showed reduced Aβ and AICD generation from recombinant APP-CTF substrates in a gene-dosedependent manner Taken together, these findings indicate a substantial loss of γ-secretase activity of the mutant allele [68]. Genetic deletion of γ-secretase complex components in mice has demonstrated that a 30% reduction in γ-secretase activity is sufficient to induce a myeloproliferative disease resembling chronic myelomonocytic leukaemia [90] These phenotypes, likely provoked by reduced NOTCH processing and signaling, have never been associated with FAD, further arguing that heterozygous expression of PSEN mutations does not result in a substantial loss of γ-secretase activity [4]. To establish improved models that faithfully reproduce the genetic and biochemical characteristics of PSEN FAD patients will be laborious and time-consuming, but it is clearly required to overcome the shortcomings of current models based on overexpression of PSEN mutants

Conclusion

Findings

Alzheimer Association