Middle-Aged Diabetic Females and Males Present Distinct Susceptibility to Alzheimer Disease-like Pathology.

Type 2 diabetes (T2D) is a highly concerning public health problem of the twenty-first century. Currently, it is estimated that T2D affects 422 million people worldwide with a rapidly increasing prevalence. During the past two decades, T2D has been widely shown to have a major impact in the brain. This, together with the cognitive decline and increased risk for dementia upon T2D, may arise from the complex interaction between normal brain aging and central insulin signaling dysfunction. Among the several features shared between T2D and some neurodegenerative disorders (e.g., Alzheimer disease (AD)), the impairment of insulin signaling may be a key link. However, these may also involve changes in sex hormones' function and metabolism, ultimately contributing to the different susceptibilities between females and males to some pathologies. For example, female sex has been pointed as a risk factor for AD, particularly after menopause. However, less is known on the underlying molecular mechanisms or even if these changes start during middle-age (perimenopause). From the above, we hypothesized that sex differentially affects hormone-mediated intracellular signaling pathways in T2D brain, ultimately modulating the risk for neurodegenerative conditions. We aimed to evaluate sex-associated alterations in estrogen/insulin-like growth factor-1 (IGF-1)/insulin-related signaling, oxidative stress markers, and AD-like hallmarks in middle-aged control and T2D rat brain cortices. We used brain cortices homogenates obtained from middle-aged (8-month-old) control Wistar and non-obese, spontaneously T2D Goto-Kakizaki (GK) male and female rats. Peripheral characterization of the animal models was done by standard biochemical analyses of blood, plasma, or serum. Steroid sex hormones, oxidative stress markers, and AD-like hallmarks were given by specific ELISA kits and colorimetric techniques, whereas the levels of intracellular signaling proteins were determined by Western blotting. Albeit the high levels of plasma estradiol and progesterone observed in middle-aged control females suggested that they were still under their reproductive phase, some gonadal dysfunction might be already occurring in T2D ones, hence, anticipating their menopause. Moreover, the higher blood and lower brain cholesterol levels in female rats suggested that its dysfunctional uptake into the brain cortex may also hamper peripheral estrogen uptake and/or its local brain steroidogenic metabolism. Despite the massive drop in IGF-1 levels in females' brains, particularly upon T2D, they might have developed some compensatory mechanisms towards the maintenance of estrogen, IGF-1, and insulin receptors function and of the subsequent Akt- and ERK1/2-mediated signaling. These may ultimately delay the deleterious AD-like brain changes (including oxidative damage to lipids and DNA, amyloidogenic processing of amyloid precursor protein and increased tau protein phosphorylation) associated with T2D and/or age (reproductive senescence) in female rats. By demonstrating that differential sex steroid hormone profiles/action may play a pivotal role in brain over T2D progression, the present study reinforces the need to establish sex-specific preventive and/or therapeutic approaches and an appropriate time window for the efficient treatment against T2D and AD.

The role of endoplasmic reticulum in amyloid precursor protein processing and trafficking: implications for Alzheimer's disease.

The endoplasmic reticulum (ER) is the principal organelle responsible for the proper folding/processing of nascent proteins and perturbed ER function leads to a state known as ER stress. Mammalian cells try to overcome ER stress through a set of protein signaling pathways and transcription factors termed the unfolded protein response (UPR). However, under unresolvable ER stress conditions, the UPR is hyperactivated inducing cell dysfunction and death. The accumulation of misfolded proteins in the brain of Alzheimer's disease (AD) patients suggests that alterations in ER homeostasis might be implicated in the neurodegenerative events that characterize this disorder. This review discusses the involvement of ER stress in the pathogenesis of AD, focusing the processing and trafficking of the AD-related amyloid precursor protein (APP) during disease development. The potential role of ER as a therapeutic target in AD will also be debated.

Hyperglycemia, hypoglycemia and dementia: role of mitochondria and uncoupling proteins.

Diabetes mellitus is one of the most prevalent chronic diseases. Since glucose is the main fuel of the brain, its levels should be maintained within a narrow range to ensure normal brain function. Indeed, the literature shows that uncontrolled blood glucose levels, whether too high or too low, impact brain structure and function potentiating cognitive impairment. Uncoupling proteins (UCPs) are a family of mitochondrial anion carrier proteins located on the inner mitochondrial membrane, and their primary function is to leak protons from the intermembrane space into the mitochondrial matrix. The specific role of neuronal UCPs has been widely discussed and although there is no general agreement, there is a strong conviction that these proteins may be involved in the defense against mitochondrial reactive oxygen species (ROS) production and, consequently, protecting against oxidative damage. The generation of ROS is increasingly recognized as playing an important role in diabetes, neurodegenerative disorders and aging where mitochondria are both sources and targets of these reactive species. This review examines the neurodegenerative events associated with diabetes, highlighting the role of hyperglycemia and/or hypoglycemia on cognitive function. The role of mitochondria, neuronal UCPs and their impact in central nervous system will be elucidated. Finally, we will discuss neuronal UCPs as possible therapeutic targets for the treatment of diabetes-associated central complications and neurodegenerative diseases, namely Alzheimer's and Parkinson's diseases.