Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity

Author:

Schilling Sandra,Pradhan Ajay,Heesch Amelie,Helbig Andrea,Blennow Kaj,Koch Christian,Bertgen Lea,Koo Edward H.,Brinkmalm Gunnar,Zetterberg Henrik,Kins Stefan,Eggert Simone

Abstract

AbstractThe amyloid precursor protein (APP) is a key player in Alzheimer`s disease (AD) and the precursor of the Aβ peptide, which is generated by consecutive cleavages of β- and γ-secretases. Familial Alzheimer’s disease (FAD) describes a hereditary subgroup of AD that represents a low percentage of AD cases with an early onset of the disease. Different APP FAD mutations are thought to have qualitatively different effects on its proteolytic conversion. However, few studies have explored the pathogenic and putative physiological differences in more detail. Here, we compared different FAD mutations, located at the β- (Swedish), α- (Flemish, Arctic, Iowa) or γ-secretase (Iberian) cleavage sites. We examined heterologous expression of APP WT and FAD mutants in non-neuronal cells and their impact on presynaptic differentiation in contacting axons of co-cultured neurons. To decipher the underlying molecular mechanism, we tested the subcellular localization, the endocytosis rate and the proteolytic processing in detail by immunoprecipitation–mass spectrometry. Interestingly, we found that only the Iberian mutation showed altered synaptogenic function. Furthermore, the APP Iowa mutant shows significantly decreased α-secretase processing which is in line with our results that APP carrying the Iowa mutation was significantly increased in early endosomes. However, most interestingly, immunoprecipitation–mass spectrometry analysis revealed that the amino acid substitutions of APP FAD mutants have a decisive impact on their processing reflected in altered Aβ profiles. Importantly, N-terminally truncated Aβ peptides starting at position 5 were detected preferentially for APP Flemish, Arctic, and Iowa mutants containing amino acid substitutions around the α-secretase cleavage site. The strongest change in the ratio of Aβ40/Aβ42 was observed for the Iberian mutation while APP Swedish showed a substantial increase in Aβ1–17 peptides. Together, our data indicate that familial AD mutations located at the α-, β-, and γ-secretase cleavage sites show considerable differences in the underlying pathogenic mechanisms.

Funder

Swedish State Support for Clinical Research

Alzheimer Forschung Initiative

Deutsche Forschungsgemeinschaft

BioComp

TU Nachwuchsring

Swedish Research Council

European Union's Horizon Europe research and innovation programme

Alzheimer's Drug Discovery Foundation

AD Strategic Fund and the Alzheimer's Association

the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden

HORIZON EUROPE Marie Sklodowska-Curie Actions

UK Dementia Research Institute

Max Planck Institute for Multidisciplinary Sciences

Publisher

Springer Science and Business Media LLC

Subject

Cellular and Molecular Neuroscience,Neurology (clinical),Pathology and Forensic Medicine

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