Altered protein composition of isolated human cortical neurons in alzheimer disease

To characterize the protein composition of degenerating neurons in Alzheimer disease, enriched fractions of isolated cortical neurons from postmortem Alzheimer brain were compared by ultrastructural and biochemical techniques to neuronal isolates from aged normal controls and from patients with the nonfibrillary degenerative dementia, Huntington disease. Electron microscopy of isolated neurons showed well‐preserved organelles, including nuclear membranes, mitochondria, endoplasmic reticulum, ribosomes, and lipofuscin. Abundant paired helical filaments (PHF) were preserved in affected Alzheimer perikarya. In both sporadic and familial Alzheimer disease, sodium dodecylsulfate‐polyacrylamide gel electrophoresis revealed marked augmentation of a 20,000 mw protein (P20) in neuronal fractions from affected cortex compared to Huntington disease patients and controls. P20 was commonly increased in hippocampal, temporal, and frontal neurons but not in cortex free of PHF. The augmentation of P20 in Alzheimer disease samples appeared to correlate with the presence of PHF‐bearing neurons in the fractions. The increase in P20 in Alzheimer disease was observed in the presence of proteolysis inhibitors, in reverse‐sieved samples, and in whole cortical homogenates. Neurofilament proteins, tubulins, and a 50,000 mw protein showed no changes. In Huntington disease, marked augmentation of a 49,000 mw protein was found in striatal but not cortical homogenates. The relationship of these findings to the biochemistry of brain fibrous proteins and to the molecular pathology of Alzheimer disease is discussed.

[1]  J. Hageman,et al.  Specificity of the serine protease inhibitor, phenylmethylsulfonyl fluoride. , 1979, Biochemical and biophysical research communications.

[2]  D. Selkoe,et al.  Biochemical and immunological characterization of neurofilaments in experimental neurofibrillary degeneration induced by aluminum , 1979, Brain Research.

[3]  H. Wiśniewski,et al.  Alzheimer neurofibrillary tangles in diseases other than senile and presenile dementia , 1979, Annals of neurology.

[4]  W. Schlaepfer,et al.  CALCIUM‐DEPENDENT ALTERATIONS OF NEUROFILAMENT PROTEINS OF RAT PERIPHERAL NERVE , 1979, Journal of neurochemistry.

[5]  M. Shelanski,et al.  Intermediate filaments in nervous tissues , 1978, The Journal of cell biology.

[6]  E K Perry,et al.  Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. , 1978, British medical journal.

[7]  D. Price,et al.  Slow axonal transport of neurofilament proteins: impairment of beta,beta'-iminodipropionitrile administration. , 1978, Science.

[8]  W. Schlaepfer,et al.  Neurofilament proteins of rat peripheral nerve and spinal cord , 1978, The Journal of cell biology.

[9]  S. Korey,et al.  Phosphate Buffer Extraction Of Gliosed ALD White Matter , 2003 .

[10]  H. Wiśniewski,et al.  Chemical relationship of the paired helical filaments of Alzheimer's dementia to normal human neurofilaments and neurotubules , 1978, Brain Research.

[11]  W. Schlaepfer Immunological and ultrastructural studies of neurofilaments isolated from rat peripheral nerve , 1977, The Journal of cell biology.

[12]  W. Schlaepfer,et al.  Immunofluorescence studies of neurofilaments in the rat and human peripheral and central nervous system , 1977, The Journal of cell biology.

[13]  J. Spillane,et al.  Selective vulnerability of neurones in organic dementia , 1977, Nature.

[14]  G. Blessed,et al.  NECROPSY EVIDENCE OF CENTRAL CHOLINERGIC DEFICITS IN SENILE DEMENTIA , 1977, The Lancet.

[15]  P. Davies,et al.  SELECTIVE LOSS OF CENTRAL CHOLINERGIC NEURONS IN ALZHEIMER'S DISEASE , 1976, The Lancet.

[16]  M. Ball,et al.  NEUROFIBRILLARY TANGLES AND THE PATHOGENESIS OF DEMENTIA: A QUANTITATIVE STUDY , 1976 .

[17]  H. Wiśniewski,et al.  ULTRASTRUCTURAL STUDIES OF THE NEUROPIL & NEUROFIBRILLARY TANGLES IN ALZHEIMERʼS DISEASE & POST-TRAUMATIC DEMENTIA: 136 , 1976 .

[18]  R. Terry,et al.  CORRELATIONS AMONG NUMBERS OF NEURITIC PLAQUES, NEUROFIBRILLARY TANGLES, AND THE SEVERITY OF SENILE DEMENTIA: 135 , 1976 .

[19]  R. Katzman.,et al.  Editorial: The prevalence and malignancy of Alzheimer disease. A major killer. , 1976, Archives of neurology.

[20]  H. Wiśniewski,et al.  Neurofibrillary tangles of paired helical filaments , 1976, Journal of the Neurological Sciences.

[21]  M. Schachner,et al.  Biochemistry of the filaments of brain. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[22]  D. Dahl,et al.  Glial fibrillary acidic protein from bovine and rat brain. Degradation in tissues and homogenates. , 1976, Biochimica et biophysica acta.

[23]  R. Terry Dementia. A brief and selective review. , 1976, Archives of neurology.

[24]  B. Anderton,et al.  Neurofilament disguise, destruction and discipline , 1975, Nature.

[25]  M. Kainosho,et al.  Effects of structural defects in sonicated phospholipid vesicles on fusion and ion permeability , 1975, Nature.

[26]  R. Lasek,et al.  The slow component of axonal transport. Identification of major structural polypeptides of the axon and their generality among mammalian neurons , 1975, The Journal of cell biology.

[27]  H. Wiśniewski,et al.  Protein changes in senile dementia. , 1974, Brain research.

[28]  W. Ellis,et al.  Presenile dementia in Down's syndrome , 1974, Neurology.

[29]  K. Iqbal,et al.  Isolation of neurons and glial cells from normal and pathological human brains. , 1972, Brain research.

[30]  S. Bessman,et al.  Protein determination by Lowry's method in the presence of sulfhydryl reagents. , 1972, Analytical biochemistry.

[31]  L. Eng,et al.  Localization of the glial fibrillary acidic protein in astrocytes by immunofluorescence. , 1972, Brain research.

[32]  M. Shelanski,et al.  Isolation of Filaments from Brain , 1971, Science.

[33]  C. Raine,et al.  The ultrastructure of purified preparations of neurons and glial cells. , 1971, Brain research.

[34]  Alistair Burns,et al.  Observations on the brains of demented old people. B.E. Tomlinson, G. Blessed and M. Roth, Journal of the Neurological Sciences (1970) 11, 205–242; (1968) 7, 331–356 , 1997 .

[35]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[36]  W. Norton,et al.  Neuronal Soma and Whole Neuroglia of Rat Brain: A New Isolation Technique , 1970, Science.

[37]  M. Roth,et al.  The Association Between Quantitative Measures of Dementia and of Senile Change in the Cerebral Grey Matter of Elderly Subjects , 1968, British Journal of Psychiatry.

[38]  I. Evangelista,et al.  THE CONTRIBUTION OF ALTERED SYNAPSES IN THE SENILE PLAQUE: AN ELECTRON MICROSCOPIC STUDY IN ALZHEIMER'S DEMENTIA , 1967, Journal of neuropathology and experimental neurology.

[39]  M. Kidd ALZHEIMER'S DISEASE--AN ELECTRON MICROSCOPICAL STUDY. , 1964, Brain : a journal of neurology.

[40]  R. Terry,et al.  ULTRASTRUCTURAL STUDIES IN ALZHEIMER'S PRESENILE DEMENTIA. , 1964, The American journal of pathology.

[41]  M. Kidd Paired Helical Filaments in Electron Microscopy of Alzheimer's Disease , 1963, Nature.

[42]  O. H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.