A recent study has linked the inability to remove reactive oxygen species, specifically the superoxide ion, and acceleration of Alzheimer's Disease symptoms in a mouse model.
Oxidative Stress
The production of reactive oxygen species (ROS) drives oxidative stress and the damage associated. A major anti-oxidant enzyme, superoxide dismutase (SOD), is one of the many ways cells are able to neutralize ROS. There are three isoforms of SOD: SOD1 (CuZn-SOD) which is located in the cytosol,nucleus, and the intermembrane space of the mitochondrias, SOD2 (Mn-SOD) which is located in the mitochondrial matrix, and SOD3(CuZn-SOD/EC-SOD) which is located in the extracellular matrix. A previous study had shown that SOD1 knockout caused increased drusen formation, which correlates with age-related macular degeneration . Drusen deposits are thought to possibly contain amyloid B oligomers, the same oligomers that are associated with Alzheimer's Disease.
SOD1 Knockout
By removing SOD1(SOD1 +/-, SOD1-/-) from the amyloid precursor protein-overexpressing mouse model of Alzheimer's Disease, several effects of oxidative damage were studied. Deficiency of SOD1 caused accelerated amyloid B oligomerization, increased tau phosphorylation, and decreased synaptophysin (a protein expressed on presynaptic vesicles). All of these correspond with the worsening of cognitive function associated with Alzheimer's. An increase in advance glycation end-products (AGEs) were seen and have been shown in other studies to possibly effect histamine release from mast cells present in the brain. Furthermore, activated microglia and astrocytes were seen to increase, associated with increase plaque formation and subsequent neuroinflammation. To further establish the significance of SOD activity in human Alzheimer's patients, levels of the three SOD isoforms were determined from human Alzheimer's patients and age-matched controls. It was found that SOD1 was significantly decreased, while SOD2/3 were unchanged.
Implications for Alzheimer's Disease
Alzheimer's is a complex neurodegenerative disease with many possible factors effecting the onset and progression of symptoms. Oxidative stress clearly plays a role, but it is still undetermined the exact role and the extent to which it participates in the pathogenesis of Alzheimer's. Identification of possible pathways to counteract the role of oxidative stress in Alzheimer's could lead to therapeutic treatments. In the case of SOD1, possible targets could be SOD1 replacement (mimetics) or dietary intake of Cu (thought to stabilize activity), although currently mouse models of Alzheimer's are the only evidence for the benefits of any treatment.
References
Murakami et al. 2011. SOD1 DEFICIENCY DRIVES AMYLOID B OLIGOMERIZATION AND MEMORY LOSS IN A MOUSE MODEL OF ALZHEIMER’S DISEASE. JBC. M111.279208.
Sick et al. 2010. Advanced glycation end products (AGEs) activate mast cells. BJP. 161:442-455.
Oxidative stress is implicated in many diseases and not only is it harmful to mitochondria, accumulation of ROS can be harmful to (like you mentioned mast cells) lymphocyte development, muscle, and adipose tissue. A few examples are listed below:
ReplyDeleteThe mitochondrial free radical theory of ageing (mFRTA) proposes that ageing is due to the accumulation of unrepaired oxidative damage, in particular to mitochondria.
Gruber J, Ng LF, Fong S, Wong YT, Koh SA, Chen CB, Shui G, Cheong WF, Schaffer S, Wenk MR, Halliwell B. Mitochondrial changes in ageing Caenorhabditis elegans--what do we learn from superoxide dismutase knockouts? PLos One. 2011, 6(5):e19444.
ROS accumulation in the mitochondria contributes to apoptosis during reperfusion ischemic injury. Ischemia triggers mitochondrial permeability transition pore, mitochondrial depolarization, and cell death during reperfusion.
Loor G, Kondapalli J, Iwase H, Chandel NS, Waypa GB, Guzy RD, Vanden Hoek TL, Schumacker PT.Mitochondrial oxidant stress triggers cell death in simulated ischemia-reperfusion. Biochim Biophys Acta. 2011, 1813(7):1382-94.
An increase in mitochondrial matrix superoxides, elevated glycolytic muscle-specific mitochondrial oxidative stress and damage reduced the muscle contractile force and reduced aerobic exercise capacity.
Lustgarten MS, Jang YC, Liu Y, Muller FL, Qi W, Steinhelper M, Brooks SV, Larkin L, Shimizu T, Shirasawa T, McManus LM, Bhattacharya A, Richardson A, Van Remmen H.Conditional knockout of Mn-SOD targeted to type IIB skeletal muscle fibers increases oxidative stress and is sufficient to alter aerobic exercise capacity. Am J Physiol Cell Physiol. 2009, 297(6):C1520-32.
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