Alzheimer's disease: Tau proteins, the promoting factors of microtubule assembly, are major components of paired helical filaments

doi:10.1016/0022-510X(86)90167-X

Journal of the Neurological Sciences

Volume 76, Issues 2–3, December 1986, Pages 173-186

https://doi.org/10.1016/0022-510X(86)90167-X Get rights and content

Abstract

A rabbit antiserum was raised against paired helical filaments (PHF). This antiserum stains specifically neurofibrillary tangles (NFT) at the light-microscopic level and PHF at the electron-microscopic level in sections of Alzheimer neocortex and hippocampus. We studied the nature of the antigens recognized by this antiserum by immunocytochemistry, immunoblots and immunoadsorption. These approaches showed that the anti-PHF specifically labels a set of low molecular weight 65-50 kDa microtubule-associated proteins, named Tau proteins, which are promoting factors of microtubule assembly. Furthermore, antisera against Tau proteins stained NFT. It is concluded that neurofibrillary tangles are very likely composed of aggregated Tau proteins. This process might be due to an abnormal Tau protein synthesis or to an unknown lesion of certain pyramidal neurons leading to an aggregation of Tau proteins.

References (36)

D.W. Cleveland et al.
Physical and chemical properties of purified Tau factor and the role of Tau in microtubule assembly
J. Mol. Biol.
(1977)
I. Grundke-Iqbal et al.
Evidence that Alzheimer neurofibrillary tangles originate from neurotubules
Lancet
(1979)
M. Kidd et al.
Senile plaque amyloid, paired helical filaments and cerebrovascular amyloid in Alzheimer's disease are all deposits of the same protein
Lancet
(1985)
J. Nunez
Microtubules and brain development: the effects of thyroid hormones
Neurochem. Int.
(1985)
M.J. Ball
Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in hippocampal cortex of aging and demented patients
A quantitative study
Acta Neuropath. (Berl.)
(1978)
L.I. Binder et al.
The distribution of Tau in the mammalian central nervous system
J. Cell. Biol.
(1985)
J.P. Brion et al.
Ultrastructural study of enriched fractions of ‘tangles’ from human patients with senile dementia of the Alzheimer type
Acta Neuropath. (Berl.)
(1984)
J.P. Brion et al.
Neurofibrillary tangles of Alzheimer's disease: an immunohistochemical study
J. Submicrosc. Cytol.
(1985)
J.P. Brion et al.
Mise en évidence de la protéine Tau au niveau des lésions de dégénérescence neurofibrillaire de la maladie d'Alzheimer
Arch. Biol. (Bruxelles)
(1985)
D. Dahl et al.
Immunostaining of neurofibrillary tangles in Alzheimer's senile dementia with a neurofilament antiserum
J. Neurosci.
(1982)

A. Defossez et al.

Les lésions histologiques de la maladie d'Alzheimer

L'Encéphale

(1986)

A. Delacourte et al.

Study of the 10 nm filament fraction isolated during the standard microtubule preparation

Biochem. J.

(1980)

K.H. El Hachimi et al.

Immunohistochimie ultrastructurale de le dégénérescence neurofibrillaire dans la maladie d'Alzheimer

A. Fellous et al.

Microtubules assembly in vitro

Purification of assembling promoting factors

Europ. J. Biochem.

(1978)

G.G. Glenner

Amyloid deposits and amyloidosis

N. Eng. J. Med.

(1980)

I. Grundke-Iqbal et al.

Alzheimer paired helical filaments: immunochemical identification of polypeptides

Acta Neuropath. (Berl.)

(1984)

I. Grundke-Iqbal et al.

Alzheimer paired helical filaments: Cross-reacting polypeptides normally present in brain

Acta Neuropath. (Berl.)

(1985)

I. Grundke-Iqbal et al.

Alzheimer paired helical filaments: Identification of polypeptides with monoclonal antibodies

Acta Neuropath. (Berl.)

(1985)

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Alzheimer's disease: Tau proteins, the promoting factors of microtubule assembly, are major components of paired helical filaments

Abstract

J. Mol. Biol.

Lancet

Lancet

Neurochem. Int.

Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in hippocampal cortex of aging and demented patients

A quantitative study

Acta Neuropath. (Berl.)

The distribution of Tau in the mammalian central nervous system

J. Cell. Biol.

Ultrastructural study of enriched fractions of ‘tangles’ from human patients with senile dementia of the Alzheimer type

Acta Neuropath. (Berl.)

Neurofibrillary tangles of Alzheimer's disease: an immunohistochemical study

J. Submicrosc. Cytol.

Mise en évidence de la protéine Tau au niveau des lésions de dégénérescence neurofibrillaire de la maladie d'Alzheimer

Arch. Biol. (Bruxelles)

Immunostaining of neurofibrillary tangles in Alzheimer's senile dementia with a neurofilament antiserum

J. Neurosci.

Les lésions histologiques de la maladie d'Alzheimer

L'Encéphale

Study of the 10 nm filament fraction isolated during the standard microtubule preparation

Biochem. J.

Immunohistochimie ultrastructurale de le dégénérescence neurofibrillaire dans la maladie d'Alzheimer

Microtubules assembly in vitro

Purification of assembling promoting factors

Europ. J. Biochem.

Amyloid deposits and amyloidosis

N. Eng. J. Med.

Alzheimer paired helical filaments: immunochemical identification of polypeptides

Acta Neuropath. (Berl.)

Alzheimer paired helical filaments: Cross-reacting polypeptides normally present in brain

Acta Neuropath. (Berl.)

Alzheimer paired helical filaments: Identification of polypeptides with monoclonal antibodies

Acta Neuropath. (Berl.)