NEUROFIBRILLARY PATHOLOGY IN ALZHEIMER DISEASE
NEUROFIBRILLARY PATHOLOGY IN ALZHEIMER DISEASE
批准号:
2837311
负责人:
GEORGE PERRY
金额:
$19.05万
依托单位国家:
美国
项目类别:
财政年份:
1990
资助国家:
美国
项目状态:
已结题
起止时间:
1990-09-01 至 2000-11-30
中文摘要
描述:(改编自申请人摘要):来自我们的研究
实验室已经证实,氧化应激和氧化蛋白
修饰是阿尔茨海默病(AD)病变的显著特征。
这些研究是#年资助期目标的直接结果。
我们确定神经原纤维缠结(NFT)具有相同的
交联型蛋白质在老年人体内的溶解特性
按晚期糖基化终末产物(年龄)计算。然后,我们展示了针对
年龄识别NFT和老年斑(SP)。当年龄修正时-t是
被引入神经母细胞瘤细胞后,脂质过氧化作用增强,
血红素加氧酶-1(HO-1)和NFkb的强氧化应激反应
注意到了。在含有NFT的神经元中,HO-1免疫反应也增加,
但在对照组的大脑中却不存在。蛋白质的直接氧化是
也见于NFT以及神经胶质细胞的神经元胞浆和胞核
阿尔茨海默病患者的神经元,但没有年龄匹配的对照组大脑,表明氧化
损伤并不局限于损伤,氧化应激可能
先于NFT和SP的形成。对此的进一步建议来自于
识别AGE加合物的单抗被提高到NFT
神经丝蛋白和t。后者,阿尔茨50,它识别一个
T的可还原(即早期)糖基化修饰是最早的标记
阿尔茨海默病的细胞骨架改变。
我们现在建议确定年龄修改的三个特征,这些特征将
对于了解它们在AD发病机制中的作用至关重要。第一,
确定哪些蛋白质被修饰,以及它们在
病变形成。第二,评估NFT和NFT年龄调整的效果
SP对蛋白水解性和吞噬作用的抗性。第三,评估
不同脑细胞类型对AGE修饰的氧化应激反应
蛋白质。这些研究将解决年龄改变是否是一种特定的
神经元细胞骨架的早期修饰及其在损伤中的作用
持久性和细胞对衰老的不同反应。
英文摘要
DESCRIPTION: (Adapted from Applicant's Abstract): Studies from our
laboratory have established that oxidative stress and oxidative protein
modification are salient features of the lesions of Alzheimer disease (AD).
These studies are a direct outcome of the aims of the funding period in
which we determined that neurofibrillary tangles (NFT) share the same
solubility properties of proteins in aged individuals, which are crosslinked
by advanced glycation endproducts (AGE). We then demonstrated antibodies to
AGE recognize NFT and senile plaques (SP). When AGE modified-t was
introduced to neuroblastoma cells, lipid peroxidation was increased and a
strong oxidative stress response by heme oxygenase-1 (HO-1) and NFkb was
noted. HO-1 immunoreactivity is also increased in NFT-containing neurons,
but is absent in brains of control cases. Direct oxidation of protein was
also found in NFT as well as neuronal cytoplasm and nuclei of glia and
neurons of AD cases but not age matched control brains indicating oxidative
damage is not restricted to the lesions and that oxidative stress likely
precedes the formation of NFT and SP. Further suggestions of this come from
monoclonal antibodies raised to NFT which recognize AGE adducts of
neurofilament proteins as well as t. The latter, Alz50, which recognizes a
reducible (i.e., early) glycation modification of t, is the earliest marker
of cytoskeletal alteration of AD.
We now propose to determine three features of the AGE modification that will
be essential to understanding their role in AD pathogenesis. First,
determine which proteins are modified and when they become modified during
lesion formation. Second, assess the effect of AGE modification of NFT and
SP on resistance to proteolysis and phagocytosis. Third, evaluate the
oxidative stress response of various brain cell types to AGE modified
proteins. These studies will address whether AGE modification is a specific
and early modification of the neuronal cytoskeleton, its role in lesion
persistence and the differential response of cells to AGE.
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Striation is the characteristic neuritic abnormality in Alzheimer disease.
条纹是阿尔茨海默病的特征性神经炎异常。
DOI:
10.1016/s0006-8993(98)01034-8
发表时间:
1998
期刊:
Brain research
影响因子:
2.9
作者:
[Velasco,ME, Smith,MA, Siedlak,SL, Nunomura,A, Perry,G]
通讯作者:
Perry,G
Development of osteopenia in ovariectomized cynomolgus monkeys (Macaca fascicularis).
去势食蟹猴(Macaca fasciculis)骨质减少的发生。
DOI:
10.1016/8756-3282(95)00318-8
发表时间:
1995
期刊:
Bone
影响因子:
4.1
作者:
[Jerome,CP, Lees,CJ, Weaver,DS]
通讯作者:
Weaver,DS
Decreased bone mass and strength in ovariectomized cynomolgus monkeys (Macaca fascicularis).
切除卵巢的食蟹猴(食蟹猴)的骨量和强度降低。
DOI:
10.1007/s002239900227
发表时间:
1997
期刊:
Calcified tissue international
影响因子:
4.2
作者:
[Jerome,CP, Turner,CH, Lees,CJ]
通讯作者:
Lees,CJ
Is oxidative damage central to the pathogenesis of Alzheimer disease?
氧化损伤是阿尔茨海默病发病机制的核心吗?
DOI:
--
发表时间:
1998
期刊:
Acta neurologica Belgica.
影响因子:
--
作者:
[Perry,G, Smith,MA]
通讯作者:
Smith,MA
PILOT 4---AGED OR ALCOHOLIC RATS AS A MODEL OF NEURAL DEGENERATION
-
批准号:6098255
-
项目类别:
-
资助金额:$0.0万
-
财政年份:1997
-
负责人:GEORGE PERRY
-
依托单位:
NEUROFIBRILLARY PATHOLOGY IN ALZHEIMERS DISEASE
-
批准号:2050709
-
项目类别:
-
资助金额:$17.41万
-
财政年份:1990
-
负责人:GEORGE PERRY
-
依托单位:
NEUROFIBRILLARY PATHOLOGY IN ALZHEIMER DISEASE
-
批准号:2001336
-
项目类别:
-
资助金额:$17.95万
-
财政年份:1990
-
负责人:GEORGE PERRY
-
依托单位:
NEUROFIBRILLARY PATHOLOGY IN ALZHEIMER DISEASE
-
批准号:2607649
-
项目类别:
-
资助金额:$18.49万
-
财政年份:1990
-
负责人:GEORGE PERRY
-
依托单位:
NEUROFIBRILLARY PATHOLOGY IN ALZHEIMER DISEASE
-
批准号:3121106
-
项目类别:
-
资助金额:$8.87万
-
财政年份:1990
-
负责人:GEORGE PERRY
-
依托单位:
NEUROFIBRILLARY PATHOLOGY IN ALZHEIMER DISEASE
-
批准号:3121107
-
项目类别:
-
资助金额:$10.03万
-
财政年份:1990
-
负责人:GEORGE PERRY
-
依托单位:
NEUROFIBRILLARY PATHOLOGY IN ALZHEIMER DISEASE
-
批准号:3121109
-
项目类别:
-
资助金额:$15.88万
-
财政年份:1990
-
负责人:GEORGE PERRY
-
依托单位:
NEUROFIBRILLARY PATHOLOGY IN ALZHEIMER DISEASE
-
批准号:3121108
-
项目类别:
-
资助金额:$11.45万
-
财政年份:1990
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负责人:GEORGE PERRY
-
依托单位:
COMMUNITY PROGRAMS FOR CLINICAL RESEARCH ON AIDS
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批准号:2297800
-
项目类别:
-
资助金额:$0.0万
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财政年份:1989
-
负责人:GEORGE PERRY
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依托单位:
AMYLOID PRECURSOR IN ALZHEIMERS DISEASE
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批准号:2049785
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项目类别:
-
资助金额:$2.9万
-
财政年份:1988
-
负责人:GEORGE PERRY
-
依托单位:
AMYLOID PRECURSOR IN ALZHEIMER DISEASE
-
批准号:3118673
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项目类别:
-
资助金额:$5.02万
-
财政年份:1988
-
负责人:GEORGE PERRY
-
依托单位:
AMYLOID PRECURSOR IN ALZHEIMER DISEASE
-
批准号:3070548
-
项目类别:
-
资助金额:$4.53万
-
财政年份:1988
-
负责人:GEORGE PERRY
-
依托单位:
AMYLOID PRECURSOR IN ALZHEIMER DISEASE
-
批准号:3070549
-
项目类别:
-
资助金额:$5.4万
-
财政年份:1988
-
负责人:GEORGE PERRY
-
依托单位:
AMYLOID PRECURSOR IN ALZHEIMER DISEASE
-
批准号:3070552
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项目类别:
-
资助金额:$6.6万
-
财政年份:1988
-
负责人:GEORGE PERRY
-
依托单位:
AMYLOID PRECURSOR IN ALZHEIMER DISEASE
-
批准号:3118675
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项目类别:
-
资助金额:$11.46万
-
财政年份:1988
-
负责人:GEORGE PERRY
-
依托单位:
AMYLOID PRECURSOR IN ALZHEIMER DISEASE
-
批准号:3118671
-
项目类别:
-
资助金额:$11.19万
-
财政年份:1988
-
负责人:GEORGE PERRY
-
依托单位:
AMYLOID PRECURSOR IN ALZHEIMER DISEASE
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批准号:3118670
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项目类别:
-
资助金额:$5.01万
-
财政年份:1988
-
负责人:GEORGE PERRY
-
依托单位:
AMYLOID PRECURSOR IN ALZHEIMER DISEASE
-
批准号:2049784
-
项目类别:
-
资助金额:$13.54万
-
财政年份:1988
-
负责人:GEORGE PERRY
-
依托单位:
AMYLOID PRECURSOR IN ALZHEIMER DISEASE
-
批准号:3070551
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项目类别:
-
资助金额:$6.7万
-
财政年份:1988
-
负责人:GEORGE PERRY
-
依托单位:
AMYLOID PRECURSOR IN ALZHEIMER DISEASE
-
批准号:3070550
-
项目类别:
-
资助金额:$6.75万
-
财政年份:1988
-
负责人:GEORGE PERRY
-
依托单位:
海外基金