Alterations in Glucose Metabolism on Cognition: A Possible Link Between Diabetes and Dementia.

The use of the carbohydrate glucose as an energetic source is essential for an adequate function of the human body. The complex regulation of this molecule involves the coordinated action of various organs such as pancreas, liver and brain. Any disruption of this physiological balance may result in a dangerous compromise of general metabolic activities increasing the possibility of developing T1DM, T2DM and possibly AD. Astrocytes convert glucose into lactate and transfer it to neurons. This lactate is essential for neuronal metabolism and for various processes including the formation of synapses, dendrites and the expression of genes involved in memory. The brain is highly susceptible to variations in glucose blood levels, and both hypoglycemia and hyperglycemia can be dangerous. Pathological hyperglycemia induces changes in plasmatic osmotic pressure, mitochondrial production of free radicals, oxidative stress and activation of neuronal apoptosis, among others. Both AD and diabetes are chronic diseases having age as an important risk factor. As the brain ages, it seems to become much more susceptible to cellular damage induced by excess of circulating glucose and this could explain the appearance of cognitive changes observed in some patients with diabetes. Excessive circulation of pro-inflammatory agents has been observed in insulin resistance and is likely that some of these mediators may cross the bloodbrain barrier and induce abnormal neuroinflammation. GSK-3 is overexpressed in diabetes and also has been reported to regulate tau phosphorylation and production of Aß peptides in the brain. Currently, diabetes (hyperglycemia) is considered as a risk factor for the development of AD. A novel therapeutic approach, using intranasal insulin and anti-diabetic medications in patients suffering from AD is being explored and is discussed in this review.

Inflammatory Mechanisms and Oxidative Stress as Key Factors Responsible for Progression of Neurodegeneration: Role of Brain Innate Immune System.

Chronic inflammation is characterized by longstanding microglial activation followed by sustained release of inflammatory mediators, which aid in enhanced nitrosative and oxidative stress. The sustained release of inflammatory mediators propels the inflammatory cycle by increased microglial activation, promoting their proliferation and thus stimulating enhanced release of inflammatory factors. Elevated levels of several cytokines and chronic neuroinflammation have been associated with many neurodegenerative disorders of central nervous system like age-related macular degeneration, Alzheimer disease, multiple sclerosis, Parkinson's disease, Huntington' disease, and tauopathies. This review highlights the basic mechanisms of neuroinflammation, the characteristics of neurodegenerative diseases, and the main immunologic responses in CNS neurodegenerative disorders. A comprehensive outline for the crucial role of microglia in neuroinflammation and neurodegeneration and the role of Toll-like receptor signalling in coexistence of inflammatory mechanisms and oxidative stress as major factors responsible for progression of neurodegeneration have also been presented.

The Innate Immunity in Alzheimer Disease- Relevance to Pathogenesis and Therapy.

The genetic, cellular, and molecular changes associated with Alzheimer disease provide evidence of immune and inflammatory processes involvement in its pathogenesis. These are supported by epidemiological studies, which show some benefit of long-term use of NSAID. The hypothesis that AD is in fact an immunologically mediated and even inflammatory pathological process may be in fact scientifically intriguing. There are several obstacles that suggest the need for more complex view, in the process of targeting inflammation and immunity in AD. In our previous studies we proposed a reliable methodology to assess innate immunity in Alzheimer patients and controls. The methodology is based on the phenomenon of human leukocytes being resistant to viral infection. The unspecific character of the resistance, dependent on interferons and tumor necrosis factor, and occurrence in cells ex vivo indicate that an in vivo mechanism of innate immunity may be involved. The above mentioned resistance could be estimated in a test based on peripheral blood leukocytes infection by vesicular stomachs virus.