Interrelationship between Changes in the Amyloid ? 42/40 Ratio and Presenilin 1 Conformation.

ABSTRACT: The ratio of the longer (i.e., A?42/A?43) to shorter (i.e. A?40) species is a critical factor determining amyloid fibril formation, neurotoxicity and progression of the amyloid pathology in Alzheimer's disease. The relative levels of the different A? species are affected by activity and conformation of the ?-secretase complex catalytic component - presenilin 1 (PS1). The enzyme exists in a dynamic equilibrium of the conformational states, with so-called "close" conformation associated with the shift of the ?-secretase cleavage towards the production of longer, neurotoxic A? species. In the current study, fluorescence lifetime imaging microscopy, spectral Förster resonance energy transfer, calcium imaging and cytotoxicity assays were utilized to explore reciprocal link between the A?42 and A?40 peptides present at various ratios and PS1 conformation in primary neurons. We report that exposure to A? peptides at a relatively high ratio of A?42/40 causes conformational change within the PS1 subdomain architecture towards the pathogenic "closed" state. Mechanistically, the A?42/40 peptides present at the relatively high ratio increase intracellular calcium levels, which were shown to trigger pathogenic PS1 conformation. This indicates that there is a reciprocal crosstalk between the extracellular A? peptides and PS1 conformation within a neuron, with A?40 showing some protective effect. The pathogenic shift within the PS1 domain architecture may further shift the production of A? peptides towards the longer, neurotoxic A? species. These findings link elevated calcium, A?42 and PS1/?-secretase conformation, and offer possible mechanistic explanation of the impending exacerbation of the amyloid pathology.

SUBMITTER: Zoltowska KM 

PROVIDER: S-EPMC5023509 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature