The Anti-Diabetic Drug Metformin Reduces BACE1 Protein Level by Interfering with the MID1 Complex

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.

Prolonged metformin treatment leads to reduced transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL/6J mice

“…Metformin has also been shown to decrease intestinal absorption of glucose [15, 16]. Studies on metformin’s effects in the central nervous system are limited and predominantly consist of in vitro studies, some of which show support for metformin as a neuroprotective agent [17], increasing hippocampal neurogenesis and enhancing cognitive function [18] however, other studies have shown evidence that metformin may increase risk of developing Alzheimer’s disease [19] and be deleterious to neuronal survival acting through its AMPK activating mechanism [20]. Most of these studies utilize a paradigm of short-term metformin treatment.…”

Insulin resistance in Alzheimer's disease

“…MFM also ameliorates AD-like molecular and neuropathological hallmarks of insulin signaling in neuronal insulin resistance in the Neuro-2a cell line (Gupta et al, 2011). In addition, MFM reduces BACE1 and, as a consequence, Aβ production in SH-SY5Y-APP neuroblastoma cells, mouse primary cortical neurons, and wild-type mice (Hettich et al, 2014). Clinical studies reported conflicting results showing a reduced rate of onset of cognitive impairment (Dominguez et al, 2012) as well as a higher risk of developing AD (Imfeld et al, 2012).…”

Metformin Enhances Osteogenesis and Suppresses Adipogenesis of Human Chorionic Villous Mesenchymal Stem Cells

“…It is considered to be an insulin-sensitizing drug that can inhibit the production of hepatic glucose and increase peripheral glucose uptake. Apart from diabetes, metformin also possesses positive effects on cardiovascular disease and nerve regeneration (Hettich et al 2014;Fung et al 2015). In recent years, the effects of metformin on bone metabolism have received considerable attention; there is a close relationship between glucose and bone metabolism (Meier et al 2016;Starup-Linde and Vestergaard 2016).…”