Transthyretin neuroprotection in Alzheimer's disease is dependent on proteolysis

The deposition of amyloid beta peptide (A beta) in the hippocampus is one of the major hallmarks of Alzheimer's disease, a neurodegenerative disorder characterized by memory loss and cognitive impairment. The modulation of A beta levels in the brain results from an equilibrium between its production from the amyloid precursor protein and removal by amyloid clearance proteins, which might occur via enzymatic (A beta-degrading enzymes) or nonenzymatic (binding/transport proteins) reactions. Transthyretin (TTR) is one of the major A beta-binding proteins acting as a neuroprotector in AD. In addition, TTR cleaves A beta peptide in vitro. In this work, we show that proteolytically active TTR, and not the inactive form of the protein, impacts on A beta fibrillogenesis, degrades neuronal-secreted A beta, and reduces A beta-induced toxicity in hippocampal neurons. Our data demonstrate that TTR proteolytic activity is required for the neuroprotective effect of the protein constituting a putative novel therapeutic target for AD. (C) 2017 Elsevier Inc. All rights reserved.