《Nature》：阿尔茨海莫氏症研究新进展
http://www.100md.com
2004年8月6日
目前仍无药物来停止或逆转阿尔茨海莫氏症所引起的神经退化进程，但大量研究工作正在开始产生成果。现在，这种疾病所涉及的细胞和分子改变已开始变得清楚，可能的治疗方法也开始从关于该疾病的实验模型的研究中出现。Mark Mattson综述了这方面的最新进展，并指出了一些有希望的新的研究领域。
Pathways towards and away from Alzheimer's disease
Slowly but surely, Alzheimer's disease (AD) patients lose their memory and their cognitive abilities, and even their personalities may change dramatically. These changes are due to the progressive dysfunction and death of nerve cells that are responsible for the storage and processing of information. Although drugs can temporarily improve memory, at present there are no treatments that can stop or reverse the inexorable neurodegenerative process. But rapid progress towards understanding the cellular and molecular alterations that are responsible for the neuron's demise may soon help in developing effective preventative and therapeutic strategies.
, 百拇医药
Figure 1 Alzheimer's disease results in shrinkage of brain regions involved in learning and memory which is correlated with major reductions in cellular energy metabolism in living patients. a, Compared with the brain of a healthy person, the brain of an Alzheimer's disease patient exhibits marked shrinkage of gyri in the temporal lobe (lower part of the brain) and frontal lobes (left part of the brain). b, Positron emission tomography (Pet) images showing glucose uptake (red and yellow indicate high levels of glucose uptake) in a living healthy person and a normal control subject. The Alzheimer's patient exhibits large decreases in energy metabolism in the frontal cortex (top of brain) and temporal lobes (sides of the brain).
, 百拇医药
Figure 2 The neurotoxic action of A
involves generation of reactive oxygen species and disruption of cellular calcium homeostasis. Interactions of A oligomers and Fe2+ or Cu+ generates H2O2. When A aggregation occurs at the cell membrane, membrane-associated oxidative stress results in lipid peroxidation and the consequent generation of 4-hydroxynonenal (4HNE), a neurotoxic aldehyde that covalently modifies proteins on cysteine, lysine and histidine residues. Some of the proteins oxidatively modified by this A-induced oxidative stress include membrane transporters (ion-motive ATPases, a glucose transporter and a glutamate transporter), receptors, GTP-binding proteins ('G proteins') and ion channels (VDCC, voltage-dependent chloride channel; NMDAR, N-methyl-D-aspartate receptor). Oxidative modifications of tau by 4HNE and other reactive oxygen species can promote its aggregation and may thereby induce the formation of neurofibrillary tangles. A can also cause mitochondrial oxidative stress and dysregulation of Ca2+ homeostasis, resulting in impairment of the electron transport chain, increased production of superoxide anion radical and decreased production of ATP. Superoxide is converted to H2O2 by the activity of superoxide dismutases (SOD) and superoxide can also interact with nitric oxide (NO) via nitric oxide synthase (NOS) to produce peroxynitrite (ONOO*). Interaction of H2O2 with Fe2+ or Cu+ generates the hydroxyl radical (OH*), a highly reactive oxyradical and potent inducer of membrane-associated oxidative stress that contributes to the dysfunction of the ER.
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Pathways towards and away from Alzheimer's disease
Slowly but surely, Alzheimer's disease (AD) patients lose their memory and their cognitive abilities, and even their personalities may change dramatically. These changes are due to the progressive dysfunction and death of nerve cells that are responsible for the storage and processing of information. Although drugs can temporarily improve memory, at present there are no treatments that can stop or reverse the inexorable neurodegenerative process. But rapid progress towards understanding the cellular and molecular alterations that are responsible for the neuron's demise may soon help in developing effective preventative and therapeutic strategies.
, 百拇医药
Figure 1 Alzheimer's disease results in shrinkage of brain regions involved in learning and memory which is correlated with major reductions in cellular energy metabolism in living patients. a, Compared with the brain of a healthy person, the brain of an Alzheimer's disease patient exhibits marked shrinkage of gyri in the temporal lobe (lower part of the brain) and frontal lobes (left part of the brain). b, Positron emission tomography (Pet) images showing glucose uptake (red and yellow indicate high levels of glucose uptake) in a living healthy person and a normal control subject. The Alzheimer's patient exhibits large decreases in energy metabolism in the frontal cortex (top of brain) and temporal lobes (sides of the brain).
, 百拇医药
Figure 2 The neurotoxic action of A
involves generation of reactive oxygen species and disruption of cellular calcium homeostasis. Interactions of A oligomers and Fe2+ or Cu+ generates H2O2. When A aggregation occurs at the cell membrane, membrane-associated oxidative stress results in lipid peroxidation and the consequent generation of 4-hydroxynonenal (4HNE), a neurotoxic aldehyde that covalently modifies proteins on cysteine, lysine and histidine residues. Some of the proteins oxidatively modified by this A-induced oxidative stress include membrane transporters (ion-motive ATPases, a glucose transporter and a glutamate transporter), receptors, GTP-binding proteins ('G proteins') and ion channels (VDCC, voltage-dependent chloride channel; NMDAR, N-methyl-D-aspartate receptor). Oxidative modifications of tau by 4HNE and other reactive oxygen species can promote its aggregation and may thereby induce the formation of neurofibrillary tangles. A can also cause mitochondrial oxidative stress and dysregulation of Ca2+ homeostasis, resulting in impairment of the electron transport chain, increased production of superoxide anion radical and decreased production of ATP. Superoxide is converted to H2O2 by the activity of superoxide dismutases (SOD) and superoxide can also interact with nitric oxide (NO) via nitric oxide synthase (NOS) to produce peroxynitrite (ONOO*). Interaction of H2O2 with Fe2+ or Cu+ generates the hydroxyl radical (OH*), a highly reactive oxyradical and potent inducer of membrane-associated oxidative stress that contributes to the dysfunction of the ER.全文
点击浏览该文件, 百拇医药