A novel function for pro SAAS as an amyloid anti‐aggregant in Alzheimer's disease

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 pro SAAS , 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 AP dE9 mice, and in the cortex of a human AD ‐affected brain, pro SAAS immunoreactivity was highly colocalized with amyloid pathology. Immunoreactive pro SAAS co‐immunoprecipitated with Aβ immunoreactivity in lysates from APdE9 mouse brains. In vitro , pro SAAS efficiently prevented the fibrillation of Aβ 1–42 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 pro SAAS in the medium of Neuro2a cells, as well as lentiviral‐mediated pro SAAS over‐expression, blocked the neurocytotoxic effect of Aβ 1–42 in Neuro2a cells. Taken together, our results suggest that pro SAAS 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 Aβ 1–42 fibrillation, and also blocks Aβ 1–42 –mediated neurotoxicity. These results suggest that proSAAS may be a novel target for neurodegenerative disease therapy.