Diabetes and Alzheimer disease, two overlapping pathologies with the same background: oxidative stress

Abstract

There are several oxidative stress-related pathways interconnecting Alzheimer's disease and type II diabetes, two public health problems worldwide. Coincidences are so compelling that it is attractive to speculate they are the same disorder. However, some pathological mechanisms as observed in diabetes are not necessarily the same mechanisms related to Alzheimer's or the only ones related to Alzheimer's pathology. Oxidative stress is inherent to Alzheimer's and feeds a vicious cycle with other key pathological features, such as inflammation and Ca(2+) dysregulation. Alzheimer's pathology by itself may lead to insulin resistance in brain, insulin resistance being an intervening variable in the neurodegenerative disorder. Hyperglycemia and insulin resistance from diabetes, overlapping with the Alzheimer's pathology, aggravate the progression of the neurodegenerative processes, indeed. But the same pathophysiological background is behind the consequences, oxidative stress. We emphasize oxidative stress and its detrimental role in some key regulatory enzymes.

Figure 1

Hyperglycemia and insulin resistance induce free radicals which are responsible for tissue damage. The main sources for free radicals are mitochondrial dysfunction, cytosolic free Ca²⁺, the vicious cycle between inflammation and OxS, and the activity of advance glycation end products, which promote the innate immune response through their receptors. These conditions produce a significant pool of free radicals, sufficient to cause OxS in the brain. Excessive amounts of ROS/RNS break the delicate regulation of key signaling and effector proteins required to maintain the homeostasis in the brain. ROS: reactive oxygen species; AGEs: advanced glycation end products.

Figure 2

Mitochondria are the main source of free radicals in neurodegenerative diseases, which is particularly true in the Alzheimer brain. The tripeptide GSH is formed in the cytosol from cysteine, glutamate, and glycine as substrates (glutamate reacts with cysteine in the presence of γ-glutamylcysteine ligase to produce γ-glutamylcysteine, which in turn reacts in a second step catalyzed by the enzyme GSH synthetase with glycine, to produce GSH). From the cytosol, GSH is distributed to the nucleus, endoplasmic reticulum (ER), and mitochondria. GSH is a key, abundant antioxidant system to control free radical overproduction in the central nervous system. As long as GSH can be replenished, a reducing intracellular environment prevails, depending on the amount of substrates for its synthesis and the proper functioning of the antiporter system, Xc⁻¹. In T2D, the polyol pathway consumes NADPH to transform glucose into sorbitol, affecting the GSH system. Conversely, the two important substrates for GSH replenishment, cysteine and glycine, are reportedly diminished in T2D. SOD: superoxide dismutase; GR: glutathione reductase; GPx: glutathione peroxidase; GSH: γ-l-glutamyl-l-cysteinyl-glycine; GSSG: oxidized glutathione; NADPH: reduced form of NADP⁺ nicotinamide adenine dinucleotide phosphate; AR: aldose reductase; SDH: sorbitol dehydrogenase.

Figure 3

T2D and metabolic NADPH sources related to GSH functioning. 6-Phosphogluconate dehydrogenase is also reduced in experimentally induced T2D. IDH: isocitrate dehydrogenase; G6PD: glucose-6-phosphate dehydrogenase; PGD: phosphogluconate dehydrogenase; ME: malic enzyme; Db: T2D; GPx: glutathione peroxidase; GSSGr: glutathione reductase.

Figure 4

Coordinated Zn bindings with cysteine residues in the catalytic and the regulatory domain of PKC. This figure was generated from pdb entry 1PTQ [95] using the UCSF Chimera package [136].