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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
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Human secreted tau increases amyloid-beta production
Jessica Bright1, Sami Hussain2, Vu Dang1
1Department of Discovery Biology, iPierian, South San Francisco, CA, USA.
Neurobiology of Aging
|December 3, 2014
Summary
Extracellular tau (eTau) fragments increase amyloid-beta (Aβ) levels by causing neuronal hyperactivity, suggesting a positive feedback loop in Alzheimer's disease pathogenesis.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Alzheimer's disease (AD) pathogenesis involves amyloid-beta (Aβ) and tau.
- Traditionally, tau pathology is considered downstream of Aβ.
- Human tau overexpression in mouse models increases Aβ plaque deposition.
Purpose of the Study:
- Investigate the role of extracellular tau (eTau) in modulating Aβ levels.
- Determine the mechanism by which tau influences Aβ production.
- Explore therapeutic potential of targeting eTau.
Main Methods:
- Affinity purification of secreted tau from patient-derived neurons.
- Liquid chromatography-mass spectrometry analysis of eTau.
- In vitro and in vivo neutralization of eTau in human tau transgenic models.
- Electrophysiological analysis of neuronal activity.
Main Results:
- Extracellular tau (eTau) consists of N-terminal fragments.
- Neutralizing eTau reduced Aβ levels in vitro and in vivo.
- Exogenous eTau increased Aβ levels in primary human cortical neurons.
- Neuronal hyperactivity mediates eTau-induced Aβ production.
- Secreted eTau was shown to cause neuronal hyperactivity.
Conclusions:
- Extracellular tau fragments (eTau) actively increase Aβ levels.
- Neuronal hyperactivity is a key mechanism linking eTau and Aβ production.
- A positive feedback loop exists where eTau exacerbates Aβ pathology in Alzheimer's disease.
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