Metformin - a Future Therapy for Neurodegenerative Diseases : Theme: Drug Discovery, Development and Delivery in Alzheimer's Disease Guest Editor: Davide Brambilla

Abstract

Type 2 diabetes mellitus (T2DM) is a complex, chronic and progressive metabolic disease, which is characterized by relative insulin deficiency, insulin resistance, and high glucose levels in blood. Esteemed published articles and epidemiological data exhibit an increased risk of developing Alzheimer's disease (AD) in diabetic pateints. Metformin is the most frequently used oral anti-diabetic drug, which apart from hypoglycaemic activity, improves serum lipid profiles, positively influences the process of haemostasis, and possesses anti-inflammatory properties. Recently, scientists have put their efforts in establishing metformin's role in the treatment of neurodegenerative diseases, such as AD, amnestic mild cognitive impairment and Parkinson's disease. Results of several clinical studies confirm that long term use of metformin in diabetic patients contributes to better cognitive function, compared to participants using other anti-diabetic drugs. The exact mechanism of metformin's advantageous activity in AD is not fully understood, but scientists claim that activation of AMPK-dependent pathways in human neural stem cells might be responsible for the neuroprotective activity of metformin. Metformin was also found to markedly decease Beta-secretase 1 (BACE1) protein expression and activity in cell culture models and in vivo, thereby reducing BACE1 cleavage products and the production of Aβ (β-amyloid). Furthermore, there is also some evidence that metformin decreases the activity of acetylcholinesterase (AChE), which is responsible for the degradation of acetylcholine (Ach), a neurotransmitter involved in the process of learning and memory. In regard to the beneficial effects of metformin, its anti-inflammatory and anti-oxidative properties cannot be omitted. Numerous in vitro and in vivo studies have confirmed that metformin ameliorates oxidative damage.

Keywords: acetylcholinesterase; alzheimer’s disease; metformin; neurodegeneration; oxidative stress.

Fig. 1

Mechanisms linking diabetes (Type 2 Diabetes Mellitus (T2DM)) and dementia. Occurrence of T2DM, as well as obesity, hypelipidaemia and hypertension are associated with and increased risk of macro- and microvascular changes, hyperglycaemia and insulin resistance giving rise to dementia (adopted from (119)).

Fig. 2

The role of insulin resistance in AD development (e.g. mitochondrial dysfunction, which contributed to neuronal death, and inflammatory process; glycosylated hemoglobin and consecutive impaired cognitive function, oxidative stress-induced β-amyloid and phosphorylated tau formations through advanced glycation end products; GSK3β - glycogen synthase kinase-3; involved in energy metabolism, promotes the hyperphosphorylation of tau (adopted from (120)).