The deposition of amyloid β peptide (Aβ) 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 Aβ 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 (Aβ-degrading enzymes) or nonenzymatic (binding/transport proteins) reactions. Transthyretin (TTR) is one of the major Aβ-binding proteins acting as a neuroprotector in AD. In addition, TTR cleaves Aβ peptide in vitro. In this work, we show that proteolytically active TTR, and not the inactive form of the protein, impacts on Aβ fibrillogenesis, degrades neuronal-secreted Aβ, and reduces Aβ-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.