Antidiabetic drug metformin (Glucophage ^R ) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription

Abstract

Epidemiological, clinical and experimental evidence suggests a link between type 2 diabetes and Alzheimer's disease (AD). Insulin modulates metabolism of ␤-amyloid precursor protein (APP) in neurons, decreasing the intracellular accumulation of ␤-amyloid (A␤) peptides, which are pivotal in AD pathogenesis. The present study investigates whether the widely prescribed insulin-sensitizing drug, metformin (Glucophage R ), affects APP metabolism and A␤ generation in various cell models. We demonstrate that metformin, at doses that lead to activation of the AMP-activated protein kinase (AMPK), significantly increases the generation of both intracellular and extracellular A␤ species. Furthermore, the effect of metformin on A␤ generation is mediated by transcriptional up-regulation of ␤-secretase (BACE1), which results in an elevated protein level and increased enzymatic activity. Unlike insulin, metformin exerts no effect on A␤ degradation. In addition, we found that glucose deprivation and various tyrphostins, known inhibitors of insulin-like growth factors/insulin receptor tyrosine kinases, do not modulate the effect of metformin on A␤. Finally, inhibition of AMP-activated protein kinase (AMPK) by the pharmacological inhibitor Compound C largely suppresses metformin's effect on A␤ generation and BACE1 transcription, suggesting an AMPK-dependent mechanism. Although insulin and metformin display opposing effects on A␤ generation, in combined use, metformin enhances insulin's effect in reducing A␤ levels. Our findings suggest a potentially harmful consequence of this widely prescribed antidiabetic drug when used as a monotherapy in elderly diabetic patients. A lzheimer's disease (AD) is a devastating neurodegenerative disorder, with aging, genetic, and environmental factors contributing to its development and progression. AD is not only characterized by pathological deposition of A␤ peptides and neurofibrillary tangles but is also associated with microgliamediated inflammation and dysregulated lipid homeostasis and glucose metabolism. Amyloid peptides are derived from sequential proteolytic cleavages of full-length amyloid precursor protein (APP) by ␤-secretase (BACE1) and ␥-secretase. Full-length APP can undergo alternative processing by ␣-secretase, releasing a soluble fragment (sAPP␣) extracellularly, which precludes A␤ formation. Compelling evidence indicates that A␤, especially the oligomers, are toxic to neurons; excessive generation and accumulation of A␤ peptides in neurons is believed to initiate the pathological cascade in AD (1-3).Epidemiological studies strongly suggest that metabolic defects correlate with the functional alterations associated with aging of the brain and with AD pathogenesis (4-11). The vast majority of AD cases are late onset and sporadic in origin with aging being the most profound risk factor. Insulin signaling is known to be involved in the process of brain aging (12)(13)(14)(15)(16)(17)(18)(19)(20). Insulin dysfunction/resistance in diabetes mellitus (DM) is not only a common syndrome ...

Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer’s Disease

“…AMPK is a highly conserved serine/threonine protein kinase and metabolic sensor expressed in most mammalian cell types. It has been proposed that AMPK regulates neurodegeneration via the upregulation of BACE1 to increase the generation of both intracellular and extracellular Ab levels 24 as well as via the direct phosphorylation of tau at Thr231 and Ser396/404. 25 Therefore, AMPK may represent a common denominator in neurodegenerative diseases and a promising target for .…”

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

“…While initial reports indicate that metformin increases the levels of brain Aβ by upregulating β-site APP cleaving enzyme 1 (BACE1) [125], some studies show that metformin attenuated AD-like changes and also reduced tau phosphorylation [126][127][128].…”

Metformin in Cancer Therapy: A New Perspective for an Old Antidiabetic Drug?

“…Of note, Chen and colleagues recently showed that metformin increased the accumulation of β-amyloid peptides, which are pivotal in Alzheimer disease, in vitro and in vivo through the AMP activated protein kinase (AMPK) pathway, an effect that could be deleterious. Nevertheless, they also showed that the combination of metformin and insulin enhances insulin's ability to reduce the β-amyloid peptide accumulation (2). In diabetic patients, metformin confers cardiovascular protection, an effect not only related to its anti-hyperglycemic effect but also to its favorable action on lipid metabolism (3).…”