Human secreted tau increases amyloid-beta production

The interaction of amyloid-beta (A beta) and tau in the pathogenesis of Alzheimer's disease is a subject of intense inquiry, with the bulk of evidence indicating that changes in tau are downstream of A beta. It has been shown however, that human tau overexpression in amyloid precursor protein transgenic mice increases A beta plaque deposition. Here, we confirm that human tau increases A beta levels. To determine if the observed changes in A beta levels were because of intracellular or extracellular secreted tau (eTau for extracellular tau), we affinity purified secreted tau from Alzheimer's disease patient-derived cortical neuron conditioned media and analyzed it by liquid chromatography-mass spectrometry. We found the extracellular species to be composed predominantly of a series of N-terminal fragments of tau, with no evidence of C-terminal tau fragments. We characterized a subset of high affinity tau antibodies, each capable of engaging and neutralizing eTau. We found that neutralizing eTau reduces A beta levels in vitro in primary human cortical neurons where exogenously adding eTau increases A beta levels. In vivo, neutralizing human tau in 2 human tau transgenic models also reduced A beta levels. We show that the human tau insert sequence is sufficient to cause the observed increase in A beta levels. Our data furthermore suggest that neuronal hyperactivity may be the mechanism by which this regulation occurs. We show that neuronal hyperactivity regulates both eTau secretion and A beta production. Electrophysiological analysis shows for the first time that secreted eTau causes neuronal hyperactivity. Its induction of hyperactivity may be the mechanism by which eTau regulates A beta production. Together with previous findings, these data posit a novel connection between tau and A beta, suggesting a dynamic mechanism of positive feed forward regulation. A beta drives the disease pathway through tau, with eTau further increasing A beta levels, perpetuating a destructive cycle. (C) 2015 The Authors. Published by Elsevier Inc. All rights reserved.