Microtubule-associated protein 2: monoclonal antibodies demonstrate the selective incorporation of certain epitopes into Alzheimer neurofibrillary tangles.

Neurofibrillary tangles (NFT) are the principal structural alteration of neuronal cell bodies in Alzheimer disease as well as in normal aging of the human brain. While the ultrastructure of these intraneuronal lesions has been extensively studied, the biochemical composition of the fibers comprising the NFT is unknown. We report the production of three monoclonal antibodies against the microtubule-associated protein 2 (MAP-2), one of which intensely labels Alzheimer NFT.

Alzheimer's disease: exposure of neurofilament immunoreactivity in SDS-insoluble paired helical filaments.

In Alzheimer's disease, neurofibrillary tangles (NFT) react with both antibodies to paired helical filaments (PHF) and certain antibodies to neurofilaments, for example, monoclonal RT97 against the 200,000 mol. wt. neurofilament protein.

Possible modifications of vimentin following acquisition of triton insolubility.

Radiolabeled vimentin after a one-hour pulse of cultured human skin fibroblasts can be detected in both soluble and insoluble fractions. The proteolytic products of newly synthesized vimentin in the insoluble fraction differ markedly in their molecular weights and isoelectric points from those of total insoluble vimentin. The newly synthesized insoluble vimentin instead displays a degradation pattern similar to that of soluble vimentin.

Alzheimer's disease: immunoreactivity of neurofibrillary tangles with anti-neurofilament and anti-paired helical filament antibodies.

The origin of the paired helical filaments (PHF) that accumulate in human neurons during aging and in Alzheimer's disease and their relationship to normal neurofilaments remain unclear. The observation that a rabbit antiserum to highly enriched PHF fractions specifically labeled PHF in Alzheimer neurofibrillary tangles but showed no reaction with neurofilaments or other normal cytoskeletal proteins led us to compare this antiserum to two monoclonal antibodies, RT97 and BF10, previously found to cross-react with tangles and with the 210,000 and 155,000 mol. wt.

Amyloid-like (Congophilic) neurofibrillary tangles do not react with neurofilament antisera in Alzheimer's cerebral cortex.

The immunohistological properties of Alzheimer's neurofibrillary tangles (NFT) were studied by immunofluorescence with neurofilament (NF) antisera and with antiserum raised to paired helical filaments (PHF) in NFT preparations, brain smears, and cryostat sections. NFT decorated by NF antisera were Congo red-negative. Conversely, PHF antisera stained Congo red-positive NFT but failed to decorate NF-positive NFT.

Antibodies to paired helical filaments in Alzheimer's disease do not recognize normal brain proteins.

During ageing of the human brain, and particularly in senile dementia of the Alzheimer type (AD), many neurones progressively accumulate abnormal cytoplasmic fibres, called paired helical filaments (PHF). Each such fibre consists of a pair of intermediate (10 nm) filaments twisted into a double helix with a periodicity of 160 nm. PHF accumulate in large perikaryal masses, called neurofibrillary tangles, and are also found in degenerating cortical neurites that form neurite plaques.

Cholinergic function in lumbar aluminum myelopathy.

To determine whether perikaryal neurofilamentous accumulation in cholinergic neurons is associated with a deficit in cholinergic function, we developed a new model of aluminum-induced neurofibrillary degeneration, referred to as focal lumbar aluminum myelopathy. The model is produced by direct intramedullary microinjection of AlCl3, which results in a characteristic neurological syndrome. Four weeks after injections, affected rabbits show extensive neurofilamentous lesions of both large and small neurons in the lumbar spinal cord, including a majority of anterior horn cells.

Characterization of postmortem human brain proteins by two-dimensional gel electrophoresis.

The proteins of membrane and cytosol fractions from frozen human postmortem brain were analyzed by two-dimensional gel electrophoresis (isoelectric range: 5.1-6.0) and both Coomassie-blue and ammoniacal silver staining.

Brain transglutaminase: in vitro crosslinking of human neurofilament proteins into insoluble polymers.

The accumulation in aged human neurons of insoluble, high molecular weight filamentous polymers apparently linked by nondisulfide covalent bonds led us to examine human brain for the presence of transglutaminase (EC 2.3.2.

Huntington's disease: changes in striatal proteins reflect astrocytic gliosis.

Huntington's disease is an autosomal dominant neuronal degeneration characterized by age-related neuronal loss principally affecting caudate and putamen and, to a lesser extent, cerebral cortex. In order to identify selective polypeptide alterations in HD brain, we analyzed unfractionated homogenates and purified neuronal perikarya from striatum and cortex of 12 control and 14 HD brains by gel electrophoresis and immunochemical techniques. SDS polyacrylamide gel electrophoresis (SDS-PAGE) revealed a 3- to 8-fold increase in a 50,000 MW (50K) protein in HD striatal homogenates.

Alzheimer's disease: insolubility of partially purified paired helical filaments in sodium dodecyl sulfate and urea.

A method is described for the partial purification of the paired helical filaments that accumulate progressively in human neurons in Alzheimer's disease (senile dementia). Paired helical filaments have unusual solubility characteristics, including insolubility in sodium dodecyl sulfate, urea, reducing agent, and guanidine, which prevent analysis of their molecular composition by gel electrophoresis. The paired helical filaments appear to contain covalent bonds other than disulfide, which cross-link individual filaments into a rigid intracellular polymer.

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

Using anti-chicken brain neurofilament antisera, Alzheimer's neurofibrillary tangles from two patients with senile dementia were stained by immunofluorescence and by the peroxidase-antiperoxidase procedure in cryostat sections of hippocampus and frontal cortex. In sections of cerebellum obtained from the same patients, the distribution of immunostaining was the same as that observed in experimental animals: Purkinje cell baskets and nerve fibers in the inner half of the molecular layer were demonstrated selectively. The immunostaining of the tangles was abolished when the antisera were absorbed by their own antigen, by bovine brain filament preparations, or by the fraction of bovine brain filament preparations nonabsorbed on anti-glial fibrillary acidic (GFA) protein immunoaffinity columns.

Hyperpathia and sensory level due to parietal lobe arteriovenous malformation.

A 30-year-old man experienced the sudden onset of prickly dysesthesia in the perineum followed by a "heavy" sensation in the left lower extremity. There was no headache. He had a hyperpathic response to pinprick and temperature testing below the T-6 dermatome on the left and a decrease of light touch below T-10, also on the left.

Myelin basic protein in Alzheimer disease neuronal fractions and mammalian neurofilament preparations.

We previously reported a marked increase of a 20,000 molecular weight (MW) protein, P20, in some neuronal fractions and whole cortical homogenates isolated from affected cortex in Alzheimer disease; P20 comigrated electrophoretically with an unidentified, major 20,000 MW protein present in human neurofilament (NF) fractions. We now report that the 20,000 MW protein is a major constituent of rodent as well as human NF fractions and that it comigrates by one- and two-dimensional gel electrophoresis with purified myelin basic protein (MBP). Peptide mapping and staining with amido black confirmed the identity of the 20,000 MW protein of mammalian NF fractions as MBP.

The anterior tarsal tunnel syndrome. Report of two cases.

Two recently encountered patients with the anterior tarsal tunnel syndrome are presented. The various aspects of this probably under-recognized syndrome are discussed. Evidence is presented that this syndrome may be the result of abnormal stretch of the deep peroneal nerve.

Specific oculomotor deficit after diazepam. II. Smooth pursuit eye movements.

Changes in smooth pursuit eye tracking of horizontal sinusoidal target movement before and after up to 10 mg oral diazepam were measured electrooculographically in diazepam-naive humans. Diazepam produced a dose-dependent reduction in gain of pursuit eye movements at target frequencies of 0.4--1.

Specific oculomotor deficit after diazepam. I. Saccadic eye movements.

Changes in saccadic eye movements before and after up to 10 mg oral diazepam were measured electrooculographically in diazepam-naive humans. Diazepam produced dose-dependent increases in saccade duration and decreases in maximum saccade velocity over a 2--36 degrees range of saccade amplitudes. The magnitude of drug-induced changes in saccade performance was proportional to the size of saccadic movement after 10 mg diazepam.

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.

Specific oculomotor deficit after acute methadone. II. Smooth pursuit eye movements.

Changes in smooth pursuit eye tracking of targets moving sinusoidally in horizontal and vertical planes before and after up to 10 mg oral methadone were measured electrooculographically in nontolerant nondependent humans. Methadone depressed the gain of horizontal tracking movements at most frequencies tested (0.2 - 1.

Specific oculomotor deficit after acute methadone. I. Saccadic eye movements.

Changes in saccadic eye movements before and after up to 10 mg oral methadone were measured electrooculographically in nontolerant nondependent humans. Undershoot of initial saccades increased with increasing size of horizontal target displacement (to 36 degrees) from a central viewing position. Dosage as low as 5 mg caused significant increase in saccade undershoot especially to target displacements greater than 10-15 degrees.

Biochemical and immunological characterization of neurofilaments in experimental neurofibrillary degeneration induced by aluminum.

In order to identify the protein composition of 10 nm neuronal filaments, we prepared enriched fractions of rabbit spinal neurons undergoing experimental neurofilamentous degeneration induced by aluminum. Electron microscopy of the isolated perikarya showed well-preserved, large perinuclear masses of neurofilaments, which were not found in similarly isolated control perikarya. Comparison of these glial-free fractions by SDS-polyacrylamide gel electrophoresis revealed several-fold augmentation in the filament-enriched neurons of proteins migrating at 68,000 and 160,000 daltons, with an additional component at 200,000 daltons.

Neurologic and cardiovascular effects of hypotension in the monkey.

Thirty monkeys were exposed to controlled systemic hypotension of different magnitudes and duration to determine factors leading to brain injury or cardiovascular failure. Fourteen monkeys developed brain injury. Of these, 6 survived indifinitely and 8 were sacrificed or died within 12-62 hours due to neurologic deterioration accompanied by respiratory failure.