Oxidative damage in the olfactory system in Alzheimer's disease

Abstract

Increased oxidative damage is a prominent and early feature of vulnerable neurons in Alzheimer's disease (AD). However, while damage to proteins, sugars, lipids, nucleic acids and organelles such as lysosomes, mitochondria, and endoplasmic reticulum are evident, the source of increased reactive oxygen species has not been determined. Furthermore, a major limitation in further determining the source, as well as finding a means to arrest damage, is the paucity of cellular models directly homologous to AD since the vulnerable neurons of the brain in AD cannot be studied in vitro. Here, we examined the olfactory epithelium in situ to see if neurons there exhibit a similar pathological oxidative balance to vulnerable neurons in AD. In biopsy specimens, (eight AD and three controls) we found that neurons, and also the surrounding epithelial cells, show an increase in oxidative damage for a subset of the markers increased in the brain of cases of AD. Lipid peroxidation and heme oxygenase-1, a stress response protein, were increased, while nucleic acid or protein oxidation, demonstrated in vulnerable neurons in AD, were not increased. These findings highlight the systemic nature of oxidative abnormalities in AD, but that different cell types may express this abnormality by a different array of oxidative stress markers, supporting the potential for using olfactory neurons or other cells derived from AD patients in culture to understand the mechanistic basis for increased oxidative damage in AD and as a model to screen compounds for therapeutic intervention.

Vascular oxidative stress in Alzheimer disease

“…Lower plasma antioxidant levels and alterations in antioxidant enzyme activities are reported in mild cognitive impairment (MCI) patients and patients at early AD stages [19,[36][37][38][39] suggesting a systemic imbalance between ROS production and antioxidant defense systems in the plasma of AD patients and this is substantiated by increases in DNA, lipid, and protein oxidation products found in blood and cerebrospinal fluid (CSF) obtained from AD patients in comparison with controls [35,40,41]. Reflecting such a systemic oxidative imbalance in AD, we also found oxidative damage in olfactory neurons and the surrounding epithelial cells from AD donors [42], and another group reported increased 8-hydroxy-deoxyguanosine (8OHdG) in the DNA of lymphocytes from AD donors [43], which inversely correlated with the plasma levels of several antioxidant carotenoids [44].…”

Altered cytological parameters in buccal cells from individuals with mild cognitive impairment and Alzheimer's disease

“…Furthermore micronuclei are a biomarker of chromosome malsegregation and tend to be elevated in lymphocytes, fibroblasts and buccal cells of AD cases (8,28,29). Other DNA damage markers such as cH2AX (DNA double strand breaks) and 8HOdG (oxidative DNA damage) were also found to be linked with AD (30)(31)(32) and previously detected in human buccal cells (33,34). Therefore, the genomic instability events observed previously may partly explain the results of increased DNA content observed in this study when measured quantitatively by LSC.…”

The olfactory vector hypothesis of neurodegenerative disease: Is it viable?

“…41 Increases in other indices of oxidative damage within the olfactory neuroepithelium of patients with AD have also been reported, including heme oxygenase-1, a stress response protein. 42 In PD, Braak and colleagues 43 present evidence that the neuropathology, notably Lewy bodies and neurites, begins within the olfactory bulb, anterior olfactory nucleus, and dorsal motor nucleus of the vagus nerve (dmX) and then advances rostrally through susceptible regions of the medulla oblongata, pontine tegmentum, midbrain, and basal forebrain. In part because the anterior olfactory structures have fewer connections than the dmX with brain regions that subsequently exhibit the next proposed stage of pathology, these authors initially believed that the dmX is the most likely starting point.…”