HUMAN BRAIN PROTEOLYSIS IN AGING & ALZHEIMER'S DISEASE
HUMAN BRAIN PROTEOLYSIS IN AGING & ALZHEIMER'S DISEASE
批准号:
3119844
负责人:
RALPH A. NIXON
金额:
$18.68万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
1988
资助国家:
美国
项目状态:
已结题
起止时间:
1988-08-01 至 1993-07-31
中文摘要
我们首次提出用新的方法来研究蛋白质水解
英文摘要
We propose to use new methods to study, for the first time, the proteolysis
of neurofilament and other cytoskeletal proteins in postmortem human brain
during normal aging and in Alzheimer's diseas (AD). In addition to
increasing our understanding of this complex process in normal and aging
brain, these experiments will provide information pertinent to the basic
mechanism underlying the formation of neurofibrillary lessions and the
degeneration of neurons in AD and other human neurodegenerative disorders.
We have obtained evidence supporting our hypothesis that proteolysis is
defective in AD brain due to abnormal proteolytic enzyme systems and/or to
abnormally modified protein substrates that are resistant to degradation.
Having developed methods to purify the four major proteinases from human
brain (Ca++-activated neural proteinase(s) [CANP]; cathepsins D and B; and
Ca++- independent neutral proteinases), we will seek age- and AD-related
abnormalities in these enzyme systems by characterizing in detail the
structural and enzymatic properties (including denaturation rates) of each
purified enzyme and its isoenzymes from matched speciments of postmortem
prefrontal isocortex from normal adults, aged individuals (Greater than 80
years) and AD patients. Interactions between various CANP forms and a
specific regulatory factor purified from brain will also be investigated.
Distribution of the activity and the content of each human brain proteinase
will be measured by radioassay and radioimmunoassay respectively, in 15-20
selected regions of control, aged, and AD brains and correlated with the
severity of neurofibrillary pathology quantitated morphometrically and
biochemically. Based on our findings that paired helical filaments (PHF)
in AD brain are resistent to digestion by brain proteinases, we will seek
differences between normal and AD brain in the structure of specific
cytoskeletal proteins by first studying the kinetics of degradation by each
purified proteinase. Using monoclonal and polyclonal antibodies to
individual NFPs and novel 2-D immunblot approaches, we will then compare in
control and AD cases the patterns of NFP-immunreactive proteolytic products
present in unincubated tissue or generated by either purified brain
proteinases in vitro or by corresponding neuronal proteinases in situ
within intact brain microslices. Finally, the susceptibility of PHF and
recently observed PHF-immunoreactive (? precursor) variant forms to
purified proteinases will be further investigated by immunoblot analyses
using anti-PHF antibodies.
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会议论文
Endosome Dysfunction in Alzheimer's Disease
-
批准号:10219146
-
项目类别:
-
资助金额:$72.66万
-
财政年份:2018
-
负责人:RALPH A. NIXON
-
依托单位:
Endosome Dysfunction in Alzheimer's Disease
-
批准号:9693399
-
项目类别:
-
资助金额:$77.6万
-
财政年份:2018
-
负责人:RALPH A. NIXON
-
依托单位:
Endosome Dysfunction in Alzheimer's Disease
-
批准号:10433977
-
项目类别:
-
资助金额:$71.15万
-
财政年份:2018
-
负责人:RALPH A. NIXON
-
依托单位:
Endosome Dysfunction in Alzheimer's Disease
-
批准号:9977870
-
项目类别:
-
资助金额:$74.12万
-
财政年份:2018
-
负责人:RALPH A. NIXON
-
依托单位:
LASER SCANNING CONFOCAL MICROSCOPE: DOWN SYNDROME, PD, & SCHIZOPHRENIA
-
批准号:7166571
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项目类别:
-
资助金额:$8.3万
-
财政年份:2005
-
负责人:RALPH A. NIXON
-
依托单位:
In VIvo Proteolysis and Axonal Transport in Tauopathy
-
批准号:6966710
-
项目类别:
-
资助金额:$27.67万
-
财政年份:2005
-
负责人:RALPH A. NIXON
-
依托单位:
AUTOPHAGY FUNCTION & DYSFUNCTION IN ALZHEIMER'S DISEASE
-
批准号:6920487
-
项目类别:
-
资助金额:$34.01万
-
财政年份:2005
-
负责人:RALPH A. NIXON
-
依托单位:
LASER SCANNING CONFOCAL MICROSCOPE: ALZHEIMER'S DISEASE
-
批准号:7166569
-
项目类别:
-
资助金额:$28.4万
-
财政年份:2005
-
负责人:RALPH A. NIXON
-
依托单位:
LASER SCANNING CONFOCAL MICROSCOPE: AGING
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批准号:7166570
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项目类别:
-
资助金额:$6.99万
-
财政年份:2005
-
负责人:RALPH A. NIXON
-
依托单位:
ADMINISTRATIVE CORE
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批准号:6920480
-
项目类别:
-
资助金额:$10.83万
-
财政年份:2005
-
负责人:RALPH A. NIXON
-
依托单位:
ANALYTICAL CORE
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批准号:6920484
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项目类别:
-
资助金额:$22.89万
-
财政年份:2005
-
负责人:RALPH A. NIXON
-
依托单位:
Laser Scanning Confocal Microscope
-
批准号:6877450
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项目类别:
-
资助金额:$43.69万
-
财政年份:2005
-
负责人:RALPH A. NIXON
-
依托单位:
Lysosomal Dysreg & Neurodeg in Alzheimer's Disease
-
批准号:6563341
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项目类别:
-
资助金额:$26.84万
-
财政年份:2002
-
负责人:RALPH A. NIXON
-
依托单位:
Lysosomal Dysreg & Neurodeg in Alzheimer's Disease
-
批准号:6410063
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项目类别:
-
资助金额:$22.84万
-
财政年份:2001
-
负责人:RALPH A. NIXON
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依托单位:
CELL AND MOLECULAR PATHOBIOLGY OF ALZHEIMER'S DISEASE
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批准号:8222955
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项目类别:
-
资助金额:$199.59万
-
财政年份:2000
-
负责人:RALPH A. NIXON
-
依托单位:
NEURONAL & VASCULAR PATHOBIOLOGY IN ALZHEIMER'S DISEASE
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批准号:6693326
-
项目类别:
-
资助金额:$145.34万
-
财政年份:2000
-
负责人:RALPH A. NIXON
-
依托单位:
Lysosomal Dysreg & Neurodeg in Alzheimer's Disease
-
批准号:6325031
-
项目类别:
-
资助金额:$22.84万
-
财政年份:2000
-
负责人:RALPH A. NIXON
-
依托单位:
NEURONAL & VASCULAR PATHOBIOLOGY IN ALZHEIMER'S DISEASE
-
批准号:6039302
-
项目类别:
-
资助金额:$137.04万
-
财政年份:2000
-
负责人:RALPH A. NIXON
-
依托单位:
NEURONAL & VASCULAR PATHOBIOLOGY IN ALZHEIMER'S DISEASE
-
批准号:6624603
-
项目类别:
-
资助金额:$124.18万
-
财政年份:2000
-
负责人:RALPH A. NIXON
-
依托单位:
NEURONAL & VASCULAR PATHOBIOLOGY IN ALZHEIMER'S DISEASE
-
批准号:6486929
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项目类别:
-
资助金额:$11.34万
-
财政年份:2000
-
负责人:RALPH A. NIXON
-
依托单位:
海外基金