SEARCH

SEARCH BY CITATION

Keywords:

  • proSAAS;
  • protein aggregation;
  • Alzheimer's disease;
  • chaperone

Abstract

Thumbnail image of graphical abstract

Neurodegenerative diseases such as Alzheimer's disease (AD) are characterized by an abnormal aggregation of misfolded beta-sheet rich proteins such as β-amyloid (Aβ). Various ubiquitously expressed molecular chaperones control the correct folding of cellular proteins and prevent the accumulation of harmful species. We here describe a novel anti-aggregant chaperone function for the neuroendocrine protein proSAAS, an abundant secretory polypeptide that is widely expressed within neural and endocrine tissues and which has previously been associated with neurodegenerative disease in various proteomics studies. In the brains of 12-month-old APdE9 mice, and in the cortex of a human AD-affected brain, proSAAS immunoreactivity was highly colocalized with amyloid pathology. Immunoreactive proSAAS co-immunoprecipitated with Aβ immunoreactivity in lysates from APdE9 mouse brains. In vitro, proSAAS efficiently prevented the fibrillation of Aβ1–42 at molar ratios of 1 : 10, and this anti-aggregation effect was dose dependent. Structure-function studies showed that residues 97–180 were sufficient for the anti-aggregation function against Aβ. Finally, inclusion of recombinant proSAAS in the medium of Neuro2a cells, as well as lentiviral-mediated proSAAS over-expression, blocked the neurocytotoxic effect of Aβ1–42 in Neuro2a cells. Taken together, our results suggest that proSAAS may play a role in Alzheimer's disease pathology.

In this study, we describe a novel anti-aggregant function for the neuroendocrine protein, proSAAS. We found that proSAAS co-localizes with Aβ in Alzheimer's disease-affected brains, and co-immunoprecipitates with Aβ in brain extracts. In vitro, proSAAS efficiently prevents Aβ1–42 fibrillation, and also blocks Aβ1–42–mediated neurotoxicity. These results suggest that proSAAS may be a novel target for neurodegenerative disease therapy.