| First Author | Bright J | Year | 2015 |
| Journal | Neurobiol Aging | Volume | 36 |
| Issue | 2 | Pages | 693-709 |
| PubMed ID | 25442111 | Mgi Jnum | J:219521 |
| Mgi Id | MGI:5621101 | Doi | 10.1016/j.neurobiolaging.2014.09.007 |
| Citation | Bright J, et al. (2015) Human secreted tau increases amyloid-beta production. Neurobiol Aging 36(2):693-709 |
| abstractText | The interaction of amyloid-beta (Abeta) 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 Abeta. It has been shown however, that human tau overexpression in amyloid precursor protein transgenic mice increases Abeta plaque deposition. Here, we confirm that human tau increases Abeta levels. To determine if the observed changes in Abeta 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 Abeta levels in vitro in primary human cortical neurons where exogenously adding eTau increases Abeta levels. In vivo, neutralizing human tau in 2 human tau transgenic models also reduced Abeta levels. We show that the human tau insert sequence is sufficient to cause the observed increase in Abeta 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 Abeta 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 Abeta production. Together with previous findings, these data posit a novel connection between tau and Abeta, suggesting a dynamic mechanism of positive feed forward regulation. Abeta drives the disease pathway through tau, with eTau further increasing Abeta levels, perpetuating a destructive cycle. |
