Elevated risk of type 2 diabetes for development of Alzheimer disease: a key role for oxidative stress in brain

Abstract

Alzheimer disease (AD) is the most common form of dementia among the elderly and is characterized by progressive loss of memory and cognition. Epidemiological data show that the incidence of AD increases with age and doubles every 5 years after 65 years of age. From a neuropathological point of view, amyloid-β-peptide (Aβ) leads to senile plaques, which, together with hyperphosphorylated tau-based neurofibrillary tangles and synapse loss, are the principal pathological hallmarks of AD. Aβ is associated with the formation of reactive oxygen (ROS) and nitrogen (RNS) species, and induces calcium-dependent excitotoxicity, impairment of cellular respiration, and alteration of synaptic functions associated with learning and memory. Oxidative stress was found to be associated with type 2 diabetes mellitus (T2DM), which (i) represents another prevalent disease associated with obesity and often aging, and (ii) is considered to be a risk factor for AD development. T2DM is characterized by high blood glucose levels resulting from increased hepatic glucose production, impaired insulin production and peripheral insulin resistance, which close resemble to the brain insulin resistance observed in AD patients. Furthermore, growing evidence suggests that oxidative stress plays a pivotal role in the development of insulin resistance and vice versa. This review article provides molecular aspects and the pharmacological approaches from both preclinical and clinical data interpreted from the point of view of oxidative stress with the aim of highlighting progresses in this field.

Keywords: Alzheimer disease; Heme oxygenase 1 and biliverdin reductase; Insulin; Oxidative stress; Protein oxidation; Type-2 diabetes mellitus and insulin resistance.

Figure 1. Increased oxidative stress levels as a central event driving insulin resistance in Alzheimer disease brain

Persistently high levels of circulating insulin (as observed in the first phase of T2DM) may exert a negative influence on memory and other cognitive functions by down regulation of insulin receptors (IR) at the blood brain barrier and consequent reduced insulin transport into the brain (as observed in AD), thus leading to insulin resistance. From a molecular point of view, the lack of interaction between insulin and IR is associated with an increase of the inhibitory phosphorylation on insulin receptor substrate-1/2 (IRS1/2) on Ser312, 616 and 636, which, in turn, negatively impacts on the two main arms of insulin-mediated signaling cascade: the PI3K and the MAPK pathways, both involved in the maintenance of synaptic plasticity and cell stress response. Furthermore, turning off insulin signaling results in impaired glucose transport (reduced translocation of the glucose transporter at the plasma membrane) and metabolism thus promoting an alteration of mitochondrial processes involved in energy production. In turn, impairment of mitochondria functions leads to a vicious circle in which reduced energy production is associated with an increase of ROS and RNS responsible for the oxidative/nitrosative damage of mitochondria as well as other cellular components. In addition, increased Aβ production and accumulation, which represents a key feature of AD pathology, also promotes mitochondrial impairment. Moreover, insulin resistance-associated impairments in glucose uptake and utilization are associated with increased endoplasmic reticulum (ER) stress, which deregulate lipid metabolism, causing accumulation of toxic lipids in the brain. All these events contribute to the increased oxidative stress levels responsible of neurodegeneration observed in AD brain. Although insulin resistance and Aβ production can be considered leading causes of the rise of oxidative stress, this latter, in turn, promotes IRS-1/2 Ser-312, -616 and -636 phosphorylation as well as the oxidative damage of protein involved in glycolysis, the Krebs cycle and ATP synthesis that are crucial events in the reduction of glucose metabolism and thus insulin resistance. Finally, because insulin resistance is associated with increased Aβ production and Aβ production is postulated to be responsible for the onset of insulin resistance, it remains to be clarified whether insulin resistance is a cause, consequence, or compensatory response to Aβ-induced neurodegeneration.