Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer’s Disease Treatment

Abstract

Alzheimer’s disease (AD) is one of the most devastating brain disorders. Currently, there are no effective treatments to stop the disease progression and it is becoming a major public health concern. Several risk factors are involved in the progression of AD, modifying neuronal circuits and brain cognition, and eventually leading to neuronal death. Among them, obesity and type 2 diabetes mellitus (T2DM) have attracted increasing attention, since brain insulin resistance can contribute to neurodegeneration. Consequently, AD has been referred to “type 3 diabetes” and antidiabetic medications such as intranasal insulin, glitazones, metformin or liraglutide are being tested as possible alternatives. Metformin, a first line antihyperglycemic medication, is a 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activator hypothesized to act as a geroprotective agent. However, studies on its association with age-related cognitive decline have shown controversial results with positive and negative findings. In spite of this, metformin shows positive benefits such as anti-inflammatory effects, accelerated neurogenesis, strengthened memory, and prolonged life expectancy. Moreover, it has been recently demonstrated that metformin enhances synaptophysin, sirtuin-1, AMPK, and brain-derived neuronal factor (BDNF) immunoreactivity, which are essential markers of plasticity. The present review discusses the numerous studies which have explored (1) the neuropathological hallmarks of AD, (2) association of type 2 diabetes with AD, and (3) the potential therapeutic effects of metformin on AD and preclinical models.

The potential role of human islet amyloid polypeptide in type 2 diabetes mellitus and Alzheimer’s diseases

“…Metformin can reduce the production and aggregation of Aβ in the hippocampus and cerebral cortex by increasing the activity of IDE [ 122 ]. AD is regarded as type 3 diabetes mellitus (T3DM) due to the sharing similarity with T2DM and the development of brain IR [ 123 ]. Therefore, metformin may act in a double role in the prevention and treatment of both T2DM and AD.…”

Metformin: A Narrative Review of Its Potential Benefits for Cardiovascular Disease, Cancer and Dementia

“…This model is based on the typical pathological findings of β-amyloid plaques and neurofibrillary tangles composed of abnormal tau protein. However, the metabolic processes leading to the formation of these plaques and tangles remain poorly understood [ 102 ].…”

4-Hexylresorcinol: pharmacologic chaperone and its application for wound healing

“…Unlike class I or II HDAC, SIRT is NAD-dependent deacetylase [ 30 ]. SIRT1 has therapeutic effect on type 2 diabetes [ 57 ] and Alzheimer’s disease [ 58 ]. In case of yeast, overexpression of SIRT2 gene increases its lifespan up to 30% [ 59 ].…”