PLoS One. 2014 Jul 15;9(7):e102420.

The anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex.

Hettich MM, Matthes F, Ryan DP, Griesche N, Schröder S, Dorn S, Krauβ S, Ehninger D.

Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Bonn, Germany.

 

Abstract

Alzheimer’s disease (AD), the most common form of dementia in the elderly, is characterized by two neuropathological hallmarks: senile plaques, which are composed of Aβ peptides, and neurofibrillary tangles, which are composed of hyperphosphorylated TAU protein. Diabetic patients with dysregulated insulin signalling are at increased risk of developing AD. Further, several animal models of diabetes show increased Aβ expression and hyperphosphorylated tau. As we have shown recently, the anti-diabetic drug metformin is capable of dephosphorylating tau at AD-relevant phospho-sites. Here, we investigated the effect of metformin on the main amyloidogenic enzyme BACE1 and, thus, on the production of Aβ peptides, the second pathological hallmark of AD. We find similar results in cultures of primary neurons, a human cell line model of AD and in vivo in mice. We show that treatment with metformin decreases BACE1 protein expression by interfering with an mRNA-protein complex that contains the ubiquitin ligase MID1, thereby reducing BACE1 activity. Together with our previous findings these results indicate that metformin may target both pathological hallmarks of AD and may be of therapeutic value for treating and/or preventing AD.

PMID: 25025689

 

Supplements:

The biguanide metformin has been used for decades in the treatment of type 2 diabetes mellitus (DM) and is currently the most widely prescribed anti-hyperglycaemic drug. Although the exact mechanisms are largely unknown, epidemiological and biological data support a link between diabetes mellitus (DM) and Alzheimer’s disease (AD): Persons with diabetes type 2 are at increased risk of developing AD, whereas insulin signalling resistance, a typical hallmark of DM, is also found in AD patients.

Brains of AD patients display two main pathological hallmarks: neurofibrillary tangles, consisting of hyperphosphorylated tau protein, and amyloid plaques, containing Aβ peptides. Previous reports showed that metformin is capable of inducing the protein-phosphatase PP2A, which leads to dephosphorylation of tau protein (Kickstein et al., PNAS 2010). In the current study, we wanted to investigate whether metformin can also target the second pathological hallmark of AD, the generation of toxic Aβ peptides.

Aβ peptides are formed by sequential cleavage of the amyloid precursor protein (APP). Cleavage by the α-secretases, followed by the γ-secretase, results in non-toxic fragments. In pathological condition, APP cleavage by the β-secretase BACE1 is increased, resulting in C-terminal fragments of which the γ-secretase then generates toxic Aβ peptides. In the current study we show that treatment of primary cortical neurons with metformin leads to reduced BACE1 protein levels and thus reduced β-secretase activity. Furthermore, we demonstrate in an APP-overexpressing neuronal cell line that metformin treatment reduces the production of BACE1 cleavage products. Importantly, we found that the administration of metformin to mice via the drinking water also resulted in a reduction of BACE1 protein in vivo.

How does metformin mediate this reduction of BACE1 protein expression? We show that the BACE1 mRNA binds to the MID1-PP2A complex, which is known to be involved in transcriptional regulation. Normally the MID1 complex enables translation by recruiting the regulatory protein S6K, which upon phospho-activation by mTOR facilitates mRNA translation. Metformin was shown to disassemble the MID1 complex. This results in the activation of the phosphatase PP2A. On the one hand, PP2A can now dephosphorylate tau protein, targeting the first major pathological hallmark of AD. On the other hand, PP2A also dephosphorylates S6K, while mTOR kinase activity is concurrently suppressed. This results in reduced translation of BACE1 mRNA and thus reduced β-secretase activity, targeting the production of Aβ peptides, the second major hallmark of AD (Fig. 1).

featured article model

Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann