Human secreted tau increases amyloid-beta production

NEUROBIOLOGY OF AGING

卷:36

Article

Bright, Jessica¹  Hussain, Sami²  Dang, Vu¹  Wright, Sarah¹  Cooper, Bonnie¹  Byun, Tony²  Ramos, Carla²  Singh, Andrew²  Parry, Graham²  Stagliano, Nancy^1,2  Griswold-Prenner, Irene¹ 

[1] iPierian, Dept Discovery Biol, San Francisco, CA USA

[2] iPierian, Dept Translat Res, San Francisco, CA USA

关键词: Secreted tau;    Extracellular tau;    eTau;    Amyloid-beta (A beta);    Neuronal hyperactivity;    Alzheimer's disease;    Feed forward mechanism;    sAPP alpha;   

DOI  :  10.1016/j.neurobiolaging.2014.09.007

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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