Diabetes Drug Prevents Alzheimer's Disease in Mouse Model

The biguanide drug metformin, which is used to treat type II diabetes, has been found to block phosphorylation of the tau proteins that are present in insoluble tangles in the brains of Alzheimer's disease patients.

Hyperphosphorylation of the tau protein can result in the self-assembly of tangles of paired helical filaments and straight filaments, which are involved in the pathogenesis of Alzheimer's disease and other tauopathies. When misfolded, this otherwise very soluble protein can form extremely insoluble aggregates that contribute to a number of neurodegenerative diseases.

Investigators at the German Center for Neurodegenerative Diseases (Munich) and their colleagues at the University of Dundee (United Kingdom) and the Max-Planck-Institute for Molecular Genetics (Berlin, Germany) were seeking drugs that would block phosphorylation of tau proteins and prevent the destruction of brain neurons.

In the current study they focused on the diabetes drug metformin, which was known to activate the enzyme protein phosphatase 2A (PP2A), the major tau phosphatase. Activation of PP2A would be expected to reverse tau hyperphosphorylation.

The investigators worked with both cell cultures - primary neurons taken from wild type and human tau transgenic mice - and in vivo with the two different lines of mice. They reported in the November 22, 2010, online edition of the journal Proceedings of the [US] National Academy of Sciences (PNAS) that metformin induced PP2A activity and reduced tau phosphorylation at PP2A-dependent epitopes in vitro and in vivo. This tau dephosphorylating potency could be blocked entirely by the PP2A inhibitors okadaic acid and fostriecin, confirming that PP2A was an important mediator of the observed effects. Affinity chromatography and immunoprecipitation experiments together with PP2A activity assays indicated that metformin interfered with the binding properties of the catalytic subunit of PP2A and thereby influenced PP2A activity.

"So far there is no drug on the market that targets the formation of tau aggregates,” said contributing author Dr. Sybille Krauss, a researcher at the German Center for Neurodegenerative Diseases. "If we can confirm that metformin shows also an effect in humans, it is certainly a good candidate for an effective therapy on Alzheimer's diseases.”

Related Links:
German Center for Neurodegenerative Diseases
University of Dundee
Max-Planck-Institute for Molecular Genetics