The Therapeutic Potential of Metformin in Neurodegenerative Diseases

Abstract

The search for treatments for neurodegenerative diseases is a major concern in light of today's aging population and an increasing burden on individuals, families, and society. Although great advances have been made in the last decades to understand the underlying genetic and biological cause of these diseases, only some symptomatic treatments are available. Metformin has long since been used to treat Type 2 Diabetes and has been shown to be beneficial in several other conditions. Metformin is well-tested in vitro and in vivo and an approved compound that targets diverse pathways including mitochondrial energy production and insulin signaling. There is growing evidence for the benefits of metformin to counteract age-related diseases such as cancer, cardiovascular disease, and neurodegenerative diseases. We will discuss evidence showing that certain neurodegenerative diseases and diabetes are explicitly linked and that metformin along with other diabetes drugs can reduce neurological symptoms in some patients and reduce disease phenotypes in animal and cell models. An interesting therapeutic factor might be how metformin is able to balance survival and death signaling in cells through pathways that are commonly associated with neurodegenerative diseases. In healthy neurons, these overarching signals keep energy metabolism, oxidative stress, and proteostasis in check, avoiding the dysfunction and neuronal death that defines neurodegenerative disease. We will discuss the biological mechanisms involved and the relevance of neuronal vulnerability and potential difficulties for future trials and development of therapies.

Keywords: Alzheimer's disease; Parkinson's disease; aging; diabetes; metformin; mitochondria; neurodegeneration.

Figure 1

Timeline of major advances in the treatment of Parkinson's disease and Alzheimer's disease in the last century. AADC, Aromatic L-amino acid decarboxylase; AChE, Acetylcholinesterase; GLP-1, Glucagone-like Peptide 1; HCL, Hydrochloride; MAO-B, Monoamine oxidase B; NMDAR, N-Methyl-D-Aspartate Receptor.

Figure 2

Metformin's potential as a neuroprotective agent. Metformin can counteract protein hyperphosphorylation, oxidative stress and neuroinflammation, processes known to drive neurodegeneration. Metformin can act on neurons, but also targets astrocytes and microglia. Consequently, metformin can influence inflammatory status, along with glucose metabolism in the entire brain and thereby reduce neuroinflammation and act as an antioxidant, leading to protein dephosphorylation. PPP, Pentose phosphate pathway.

Figure 3

Cellular targets of metformin. Metformin inhibits mitochondrial complex I, thereby increasing AMP/ATP ratio. This lack of energy leads to an activation of AMPK, which, amongst others, inhibits mTor signaling. Furthermore, metformin can activate PP2A and inhibit neuroinflammatory processes. Results of these events are reduced production of pro-inflammatory cytokines and reactive oxygen species (ROS), decreased oxidative stress, inhibition of protein synthesis and augmented autophagy of toxic oligomers. Additionally, protein dephosphorylation, protein aggregation, and cell death are affected.

Figure 4

The overlapping actions of metformin and rapamycin. Rapamycin acts by directly inhibiting mTOR and therefore translation regulation, which has a major influence of highly regulated processes such as mitochondrial biogenesis and autophagy. Metformin acts indirectly on the mTOR pathway through inhibition of complex I and activation of AMPK signaling. Metformin also reduces reactive oxygen species (ROS) via inhibitory action on complex I and NAD(P)H oxidase having an overall effect as a redox regulator. Downstream of metformin action, low level ROS can indirectly trigger signals for mitochondrial biogenesis and turnover of organelles and proteins via autophagy. Vice versa, maintenance of healthy mitochondrial networks involving autophagy and mitochondrial biogenesis further reduces build-up of damaging levels of ROS.