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.
Highlights
There are 44 million people dealing with dementia, being the second leading cause of death in people aged 70 and over [1,2,3,4]
African American and white patients, with data taken from Veterans Health Administration (VHA) medical record, Scherrer and colleagues showed that the administration of metformin decreases the risk of dementia by 29% and 40% in African American patients aged 65 to 74 years and 50 to 64 years, respectively
The maintenance of thin and mushroom spine populations combined with cumulative increased spine extent in the dorsal-lateral-prefrontal-cortex (DLPFC) distinguish cognitively normal older individuals with Alzheimer’s disease (AD) pathology from patients with AD dementia [134]. This changes may be linked to the mild cognitive impairment (MCI) that can be detected early in AD patients [134,135,136], confirming that synaptic loss is key to the development of the disease [60] and supplying cellular evidence that dendritic spine remodeling could be a process of cognitive resilience
Summary
There are 44 million people dealing with dementia, being the second leading cause of death in people aged 70 and over [1,2,3,4]. PS1 and PS2 are two proteins that constitute the catalytic core of γ-secretase These gene mutations—including APP, PS1, and PS2—belong to the familial form of AD and have been shown to increase the development of amyloid-β (Aβ) leading to an increase in the. TREM2 regulates the function of microglia in LOAD and other neurodegenerative diseases, and participates in inflammatory responses and metabolism, either alone or in close association with other molecules, such as APOE [15]. Type two diabetes mellitus (T2DM) and LOAD have become worldwide pandemics, with recent projections indicating that they will get worse in the coming decades In this respect, obesity, T2DM and associated comorbidities have been described to be involved in the development of LOAD [14]. The intersection between the molecular pathways of these two diseases could give birth to the appearance of the cognitive anomalies of LOAD patients with underlying T2DM [22,23,24,25]
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