Insulin signaling, glucose metabolism and mitochondria: Major players in Alzheimer's disease and diabetes interrelation

Abstract

Many epidemiological studies have shown that diabetes, particularly type 2 diabetes, significantly increases the risk to develop Alzheimer's disease. Both diseases share several common abnormalities including impaired glucose metabolism, increased oxidative stress, insulin resistance and deposition of amyloidogenic proteins. It has been suggested that these two diseases disrupt common cellular and molecular pathways and each disease potentiates the progression of the other. This review discusses clinical and biochemical features shared by Alzheimer's disease and diabetes, giving special attention to the involvement of insulin signaling, glucose metabolism and mitochondria. Understanding the key mechanisms underlying this deleterious interaction may provide opportunities for the design of effective therapeutic strategies.

Introduction

With the ageing of the population in the developed world and increasing life expectancy, the looming epidemic of age-related metabolic and neurodegenerative diseases is becoming a growing problem around the globe. Both Alzheimer's disease (AD) and diabetes mellitus, two chronic and age-related diseases, have attained epidemic proportions. AD is the most common form of dementia, affecting approximately 35 million people worldwide (Querfurth and LaFerla, 2010). The prevalence of AD increases exponentially with age, rising from 3% in people aged 65–74 to almost 50% in people aged 85 or older (Pahnke et al., 2009). Additionally, it has been predicted that in 2050 more than 140 million people worldwide will suffer from AD (Pahnke et al., 2009). Similarly, diabetes mellitus is one of the most prevalent metabolic disorders, with the total number of affected people projected to rise from 171 million in 2000 to 366 million in 2030 (Wild et al., 2004).

AD is characterized clinically by progressive memory loss and a gradual decline in cognitive function culminating in the premature death of the individual typically 3–9 years after diagnosis (Querfurth and LaFerla, 2010). The pathological features of the disease are the presence of intraneuronal neurofibrillary tangles (NFTs) mainly composed of hyperphosphorylated tau protein and the massive deposition of aggregated amyloid β (Aβ) peptide in the extracellular space as senile plaques (Castellani et al., 2010, Goedert and Spillantini, 2006, Moreira et al., 2009). AD is also characterized by severe neuronal atrophy, which initially appears in the entorhinal region and the temporal lobe, before progressing to the limbic system and subsequently to major areas of the neocortex (Braak and Braak, 1995). There are two forms of AD: the rare familial form (fAD), which is entirely genetic and the more common form that is sporadic (sAD) in origin. The minority of AD cases is of early onset and occurs due to the inheritance of autosomal dominant mutations in three genes: amyloid β precursor protein (APP), presenilin-1 (PS1), and presenilin-2 (PS2) (Rocchi et al., 2003). The great majority of AD cases occur sporadically at a late stage in life, with aging, type 2 diabetes (T2D) and apolipoprotein E4 (APOE4) as the main non-genetic and genetic risk factors (Corder et al., 1993, Hoyer, 2004, Irie et al., 2008, Kivipelto et al., 2002, Luchsinger et al., 2007, Ott et al., 1999).

Diabetes mellitus is a complex metabolic disorder mainly characterized by chronic hyperglycemia and associated with long-term damage, dysfunction, and failure of various organs, including the brain, heart, eyes and kidneys. Two major forms of diabetes mellitus are known: type 1 (T1D) and T2D, with the latter accounting for about 90% of all cases. Diabetes has been posited as a cause of brain atrophy, white matter abnormalities, cognitive impairment, and as a risk factor for dementia (Akisaki et al., 2006, den Heijer et al., 2003, Manschot et al., 2006, Schmidt et al., 2004, Toth et al., 2007). T1D results from the autoimmune destruction of pancreatic β-cells leading to the absolute deficiency of insulin production. Impaired cognitive performance (i.e. decline in learning, memory, problem solving, and mental flexibility) has been observed in T1D subjects (Biessels et al., 2008, Brands et al., 2005) suggesting a detrimental effect of cerebral hyperglycemia, and/or hypoinsulinemia. Along with these deficits, postmortem studies revealed pronounced degeneration of cerebral cortex and neuronal loss in T1D patients compared to age-matched nondiabetic patients (DeJong, 1977, Reske-Nielsen and Lundbaek, 1963). T2D, characterized by a reduction in the ability of insulin to stimulate glucose utilization (insulin resistance) and inadequate pancreatic β-cell insulin secretion in response to hyperglycemia, is related with a greater rate of cognitive deficits (i.e. decreased executive functions, memory skills and, processing speed) in comparison with the general population (Allen et al., 2004, Roriz-Filho et al., 2009). Studies of cerebral structure demonstrated a pronounced cortical, subcortical, and hippocampal atrophy in T2D patients (Roriz-Filho et al., 2009).

Since the first Rotterdam study suggesting an increased risk to develop dementia and AD in patients with T2D, numerous clinical and epidemiological studies were undertaken to further strengthen the interplay between T2D and AD (Kroner, 2009, Ott et al., 1999). Individuals with T2D have nearly a twofold higher risk of AD, independent of the risk for vascular dementia, than nondiabetic individuals (Kroner, 2009). Notably, a study of the Mayo Clinic Alzheimer Disease Patient Registry reported that greater than 80% of AD patients exhibit T2D or abnormal blood glucose levels (Janson et al., 2004), which suggests that these diseases may share a common pathogenetic mechanism responsible for the loss of brain cells and β-cells. Prospective and cross-sectional analyses proposed that diabetes may accelerate the onset of AD, rather than increasing the long-term risk (Pasquier et al., 2006). Furthermore, the risk of AD associated with the APOE ε4 allele has been suggested to be exacerbated by diabetes, as patients with diabetes who are ε4 carriers are twofold more prone to develop AD than nondiabetic individuals who harbor the ε4 allele (Peila et al., 2002). More recently, it was demonstrated that the ApoE ε4 allele modulates APP trafficking and processing, and inhibits Aβ clearance, which indicate that the presence of this allele increases the risk of developing AD (Sjogren et al., 2006).

Meanwhile, some studies failed to demonstrate a correlation between T2D and AD (Bucht et al., 1983, Heitner and Dickson, 1997, Nielson et al., 1996, Wolf-Klein et al., 1988). A postmortem study using brains of diabetic patients found no evidence of increased AD pathology compared to age-matched controls (Heitner and Dickson, 1997). The discrepancies between studies may be due to the current diagnostic practices. The diagnosis of diabetes in most large-scale studies relies on self-report or treatment records. However, this method may underestimate the prevalence of diabetes and exclude its prodromal state of impaired glucose tolerance, which is characterized by hyperinsulinemia and insulin resistance. Furthermore, diabetes is not optimally treated in all patients so that the weak interaction may reflect that well-controlled diabetic patients have less cerebrovascular disease and less impact on AD pathology, while poorly controlled diabetes may have a large impact on AD pathology.

Recently, much effort has been devoted to demystifying the cellular and molecular mechanisms linking diabetes and AD. The present review critically discusses the involvement of amyloidogenesis, dysfunctional insulin signaling along with abnormalities in brain glucose metabolism as critical players in the pathology of both diseases. The role of mitochondrial dysfunction and oxidative stress in the interconnection between diabetes mellitus and AD etiopathogenesis will be debated as well. Elucidation of the putative mechanisms underlying AD and diabetes interrelation could be important to establish new and feasible therapeutic interventions.