RESUMO
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.
Assuntos
Doença de Alzheimer/patologia , Diabetes Mellitus Tipo 2/patologia , Estresse Oxidativo , Doença de Alzheimer/metabolismo , Cálcio/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glutationa/metabolismo , Humanos , Inflamação/patologia , Mitocôndrias/metabolismo , NADP/metabolismo , Tiorredoxinas/metabolismoRESUMO
Amyloid-beta (Aß) pathology is related to mitochondrial dysfunction accompanied by energy reduction and an elevated production of reactive oxygen species (ROS). Monomers and oligomers of Aß have been found inside mitochondria where they accumulate in a time-dependent manner as demonstrated in transgenic mice and in Alzheimer's disease (AD) brain. We hypothesize that the internalization of extracellular Aß aggregates is the major cause of mitochondrial damage and here we report that following the injection of fibrillar Aß into the hippocampus, there is severe axonal damage which is accompanied by the entrance of Aß into the cell. Thereafter, Aß appears in mitochondria where it is linked to alterations in the ionic gradient across the inner mitochondrial membrane. This effect is accompanied by disruption of subcellular structure, oxidative stress, and a significant reduction in both the respiratory control ratio and in the hydrolytic activity of ATPase. Orally administrated melatonin reduced oxidative stress, improved the mitochondrial respiratory control ratio, and ameliorated the energy imbalance.