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Updated: Jun 21, 2026
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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Endogenous Aβ causes cell death via early tau hyperphosphorylation
G Amadoro1, V Corsetti, M T Ciotti
1Institute of Neurobiology and Molecular Medicine, CNR, Via del Fosso di Fiorano 64-65, 00143 Rome, Italy. g.amadoro@inmm.cnr.it
Neurobiology of Aging
|July 25, 2009
Summary
Early Alzheimer's disease (AD) tau changes link to amyloid pathway activation. This interaction causes neuronal dysfunction, offering new therapeutic targets for AD.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) involves amyloid-beta (Aβ) overproduction and tau hyperphosphorylation.
- Previous work identified amyloidogenic pathway activation in hippocampal neurons upon NGF withdrawal.
Purpose of the Study:
- To investigate the relationship between early tau hyperphosphorylation and the amyloidogenic pathway in neuronal cell death.
- To elucidate the mechanisms and consequences of site-specific tau modifications in an AD-like model.
Main Methods:
- Utilized NGF withdrawal in hippocampal neurons to induce AD-like conditions.
- Employed Aβ antibodies (4G8, 6E10) and secretase inhibitors to block pathological processes.
- Analyzed tau cleavage, caspase-3 and calpain-I activation, and Akt-GSK3β signaling.
- Assessed tau detachment from microtubules and mitochondrial trafficking.
Main Results:
- Observed early, transient, site-specific tau hyperphosphorylation (Ser262, Thr231) preceding apoptotic death.
- Demonstrated that Aβ antibodies or secretase inhibitors blocked tau hyperphosphorylation and cell death.
- Confirmed that tau hyperphosphorylation precedes caspase-3 and calpain-I activation.
- Showed Akt-GSK3β signaling controls tau phosphorylation.
- Found that site-specific tau hyperphosphorylation detaches tau from microtubules and impairs mitochondrial transport.
Conclusions:
- Established a direct temporal and causal link between early tau hyperphosphorylation and amyloidogenic pathway activation.
- Revealed a coordinated interplay between endogenous Aβ and tau post-translational modifications impacting neuronal function.
- Highlighted a novel mechanism contributing to neuronal compromise in AD pathogenesis.
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