Iron is an essential component of oxidative metabolism and a cofactor for a variety of enzymes. Because of its chemical properties as a transition metal, iron can serve both as an electron donor and acceptor and, as s...Iron is an essential component of oxidative metabolism and a cofactor for a variety of enzymes. Because of its chemical properties as a transition metal, iron can serve both as an electron donor and acceptor and, as such, excess levels of free iron are toxic. Given this potential for toxicity, a number of pro- teins, including transferrin, transferrin receptor, and ferritin, tightly control iron transport, uptake, and storage in the central nervous system. Patients with Parkinson＇s disease （PD） show a dramatic increase in iron content in dopaminergic neurons of the substantia nizra,展开更多
Considerable debate and controversy surround the cause（s） of AIzheimer＇s disease （AD）. To date, several theories have gained notoriety, however none is universally accepted. In this review, we provide evidence fo...Considerable debate and controversy surround the cause（s） of AIzheimer＇s disease （AD）. To date, several theories have gained notoriety, however none is universally accepted. In this review, we provide evidence for the oxidative stress-induced AD cascade that posits aged mitochondria as the critical origin of neurodegeneration in AD.展开更多
Background:In Alzheimer disease(AD),hyperphosphorylation of tau proteins results in microtubule destabilization and cytoskeletal abnormalities.Our prior ultra-morphometric studies documented a clear reduction in micro...Background:In Alzheimer disease(AD),hyperphosphorylation of tau proteins results in microtubule destabilization and cytoskeletal abnormalities.Our prior ultra-morphometric studies documented a clear reduction in microtubules in pyramidal neurons in AD compared to controls,however,this reduction did not coincide with the presence of paired helical filaments.The latter suggests the presence of compensatory mechanism(s)that stabilize microtubule dynamics despite the loss of tau binding and stabilization.Microtubules are composed of tubulin dimers which are subject to posttranslational modifications that affect the stability and function of microtubules.Methods:In this study,we performed a detailed analysis on changes in the posttranslational modifications in tubulin in postmortem human brain tissues from AD patients and age-matched controls by immunoblot and immunocytochemistry.Results:Consistent with our previous study,we found decreased levels ofα-tubulin in AD brain.Levels of tubulin with various posttranslational modifications such as polyglutamylation,tyrosination,and detyrosination were also proportionally reduced in AD brain,but,interestingly,there was an increase in the proportion of the acetylatedα-tubulin in the remainingα-tubulin.Tubulin distribution was changed from predominantly in the processes to be more accumulated in the cell body.The number of processes containing polyglutamylated tubulin was well preserved in AD neurons.While there was a cell autonomous detrimental effect of NFTs on tubulin,this is likely a gradual and slow process,and there was no selective loss of acetylated or polyglutamylated tubulin in NFT-bearing neurons.Conclusions:Overall,we suggest that the specific changes in tubulin modification in AD brain likely represent a compensatory response.展开更多
文摘Iron is an essential component of oxidative metabolism and a cofactor for a variety of enzymes. Because of its chemical properties as a transition metal, iron can serve both as an electron donor and acceptor and, as such, excess levels of free iron are toxic. Given this potential for toxicity, a number of pro- teins, including transferrin, transferrin receptor, and ferritin, tightly control iron transport, uptake, and storage in the central nervous system. Patients with Parkinson＇s disease （PD） show a dramatic increase in iron content in dopaminergic neurons of the substantia nizra,
基金supported by the National Institutes of Health(NS083385-01)the Alzheimer’s Association(IIRG-10-173358 and IIRG-10-173471)
文摘Considerable debate and controversy surround the cause（s） of AIzheimer＇s disease （AD）. To date, several theories have gained notoriety, however none is universally accepted. In this review, we provide evidence for the oxidative stress-induced AD cascade that posits aged mitochondria as the critical origin of neurodegeneration in AD.
基金by NIH grant NS083385(to X.Z.)and by Alzheimer Association grant IIRG-13-284849(to GP)by Chinese Overseas,Hong Kong and Macao Scholars Collaborated Research Fund Grant 81228007 to X.Z.by the Dr.Robert M.Kohrman Memorial Fund.
文摘Background:In Alzheimer disease(AD),hyperphosphorylation of tau proteins results in microtubule destabilization and cytoskeletal abnormalities.Our prior ultra-morphometric studies documented a clear reduction in microtubules in pyramidal neurons in AD compared to controls,however,this reduction did not coincide with the presence of paired helical filaments.The latter suggests the presence of compensatory mechanism(s)that stabilize microtubule dynamics despite the loss of tau binding and stabilization.Microtubules are composed of tubulin dimers which are subject to posttranslational modifications that affect the stability and function of microtubules.Methods:In this study,we performed a detailed analysis on changes in the posttranslational modifications in tubulin in postmortem human brain tissues from AD patients and age-matched controls by immunoblot and immunocytochemistry.Results:Consistent with our previous study,we found decreased levels ofα-tubulin in AD brain.Levels of tubulin with various posttranslational modifications such as polyglutamylation,tyrosination,and detyrosination were also proportionally reduced in AD brain,but,interestingly,there was an increase in the proportion of the acetylatedα-tubulin in the remainingα-tubulin.Tubulin distribution was changed from predominantly in the processes to be more accumulated in the cell body.The number of processes containing polyglutamylated tubulin was well preserved in AD neurons.While there was a cell autonomous detrimental effect of NFTs on tubulin,this is likely a gradual and slow process,and there was no selective loss of acetylated or polyglutamylated tubulin in NFT-bearing neurons.Conclusions:Overall,we suggest that the specific changes in tubulin modification in AD brain likely represent a compensatory response.
