Local modulation of neurofilament phosphorylation, axonal caliber, and slow axonal transport by myelinating Schwann cells.

Literature regarding the biochemistry of aluminum and eight similar ions is reviewed. Close and hitherto unknown similarities were found. A hypothetical model is presented for the metabolism, based on documented direct observations of Al3+ and analogies from other ions. Main characteristics are low intestinal absorption, rapid urinary excretion, and slow tissue uptake, mostly in skeleton and reticuloendothelial cells. Intracellular Al3+ is probably first confined in the lysosomes but then slowly accumulates in the cell nucleus and chromatin. Large, long-lived cells, e.g., neurons, may be the most liable to this accumulation. In heterochromatin, Al3+ levels can be found comparable to those used in leather tannage. It is proposed that an accumulation may take place at a subcellular level without any significant increase in the corresponding tissue concentration. The possible effects of this accumulation are discussed. As Al3+ is neurotoxic, the brain metabolism is most interesting. The normal and the lethally toxic brain levels of Al3+ are well documented and differ only by a factor of 3-10. The normal brain uptake of Al3+ is estimated from data on intestinal uptake of Al3+ and brain uptake of radionuclides of similar ions administered intravenously. The uptake is very slow, 1 mg in 36 years, and is consistent with an assumption that Al3+ taken up by the brain cannot be eliminated and is therefore accumulated. The possibility that Al3+ may cause or contribute to some specific diseases, most of them related to aging, is discussed with the proposed metabolic picture in mind.

Metabolism and possible health effects of aluminum.

Aluminium, an environmentally abundant non-redox trivalent cation has long been implicated in the pathogenesis of Alzheimer's disease (AD). However, the definite mechanism of aluminium toxicity in AD is not known. Evidence suggests that trace metal homeostasis plays a crucial role in the normal functioning of the brain, and any disturbance in it can exacerbate events associated with AD. The present paper reviews the scientific literature linking aluminium with AD. The focus is on aluminium levels in brain, region-specific and subcellular distribution, its relation to neurofibrillary tangles, amyloid beta, and other metals. A detailed mechanism of the role of aluminium in oxidative stress and cell death is highlighted. The importance of complex speciation chemistry of aluminium in relation to biology has been emphasized. The debatable role of aluminium in AD and the cross-talk between aluminium and genetic susceptibility are also discussed. Finally, it is concluded based on extensive literature that the neurotoxic effects of aluminium are beyond any doubt, and aluminium as a factor in AD cannot be discarded. However, whether aluminium is a sole factor in AD and whether it is a factor in all AD cases still needs to be understood.

Aluminium in Alzheimer's disease: are we still at a crossroad?

A brief description is given of neurofibrillary changes of the paired helical filament type in a variety of chronic neurological diseases. These include subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Down syndrome, Hallervorden-Spatz disease, and lipofuscinosis. In these conditions, with the exception of Hallervorden-Spatz disease neurofibrillary changes were previously recognized but paired helical filaments were identified only in some cases. Moreover, in the present series, the age of patients at death was often younger than in previously recorded cases.

Alzheimer neurofibrillary tangles in diseases other than senile and presenile dementia.

Measurements of neuron-specific and glia-specific proteins were used to characterize chemical-induced injury to the rat CNS. Trimethyltin (TMT), a neurotoxicant that preferentially damages neurons in limbic structures, was employed to produce consistent, time-dependent, dose- related, cell type-specific alterations in CNS morphology. Brain weights and histology were used to verify the cytopathological effects of TMT. Accompanying changes in 2 synaptic vesicle-associated proteins, synapsin I and p38, and the astrocyte-associated protein, glial fibrillary acidic protein (GFAP), were measured by radioimmunoassay (RIA). Immunohistochemistry of GFAP and incorporation of 3H-thymidine into GFAP-positive astrocytes also were used to characterize astrocytic responses to TMT-induced injury. Finally, quantitative 2-dimensional PAGE was employed to detect additional proteins affected by TMT. Acute administration of TMT caused large dose- and time-dependent decreases in synapsin I and p38 in hippocampus; the same proteins were largely unaffected in a nonlimbic structure, the frontal cortex. Twelve weeks after dosing, the concentrations of synapsin I and p38 and, to a lesser extent, the absolute amount of these proteins in hippocampus had returned to near control values, findings that are suggestive of reactive synaptogenesis. TMT caused large dose- and time-dependent increases in GFAP that were not confined to hippocampus. Twelve weeks after dosing, the amounts of GFAP in hippocampus and frontal cortex had returned to near control values, findings indicative of a transient astrocytic response to brain injury. Immunohistochemistry of GFAP revealed widespread astrocytic reactivity as a consequence of exposure to TMT, a response that resulted in part from the proliferation of astrocytes. Additional neurotypic proteins altered by TMT-induced injury included one of the neurofilament (NF) triplet proteins (p68) and a protein with the electrophoretic characteristics of neuron- specific enolase (NSE). The data indicate that measurements of neurotypic and gliotypic proteins may be used to characterize the temporal and regional patterns of neuronal and glial responses to injury.

https://www.jneurosci.org/content/jneuro/7/4/931.full.pdf

Quantitative changes in the synaptic vesicle proteins synapsin I and p38 and the astrocyte-specific protein glial fibrillary acidic protein are associated with chemical-induced injury to the rat central nervous system.

To determine whether the triplet polypeptides of neurofilaments arise by degradation of precursor, we studied the biosynthesis of neurofilament polypeptides both in vivo and in cell-free systems. Neurofilament-enriched fractions and polyribosomes were prepared from the same rabbit spinal cord homogenates. At 1 h after intracisternal administration of [34S]methionine, radiolabeled neurofilament proteins were detected in spinal cord homogenates as well as in isolated filaments. When polyribosomes from rabbit spinal cord were allowed to incorporate [35S]methionine into protein, triplet polypeptides were among the proteins labeled. Addition of spinal cord polyribosomes to rabbit reticulocyte lysates led to several cycles of translation of the spinal cord mRNA; the three neurofilament polypeptides were among the proteins synthesized in this system. The results demonstrate that the triplet polypeptides of neurofilaments are synthesized as such in the course of individual translational events and do not arise from degradation of P200 or a larger precursor.

/pdf/studies-on-the-biosynthesis-of-neurofilament-proteins-35dkt8ll2u.pdf

Studies on the biosynthesis of neurofilament proteins.

Neurofibrillary pathology: current status and research perspectives.

To identify axonal proteins which are unique constituents of neurons, the spectrum of detectable proteins of degenerating nerves has been compared with that of intact control nerves from the same animals. Wallerian degeneration was induced in rabbits by unilateral transection of the optic and sciatic nerves. Proteins of nerve homogenates were compared by sodium dodecyl sulfate-gel electrophoresis and by two- dimensional electrophoresis. Four non-myelin proteins disappear from degenerating nerve. These include the three neurofilament proteins (P68, P150, and P200) and a polypeptide with a molecular weight of about 65,000 daltons (P65) which is not associated with filaments.

https://www.jneurosci.org/content/jneuro/1/5/461.full.pdf

The loss of neuron-specific proteins during the course of Wallerian degeneration of optic and sciatic nerve

Tubulin has been found to be synthesized on both membrane-bound and free polyribosomes prepared from brain. Cell-free studies indicate that tubulin made on rough microsomes is incorporated into the endoplasmic reticulum membrane as it is synthesized. This tubulin remains associated with the membrane after sedimentation and washing. The tubulin is not removed from the membrane after stripping ribosomes from the membranes in KCl-puromycin, followed by repeated washing by either sedimentation or flotation in 0.05 M-KCl. The membrane tubulin is partially susceptible to proteolysis by trypsin and chymotrypsin: beta-tubulin is more accessible to the proteases than in alpha-tubulin. Nonionic detergents extract mostly beta-tubulin from the microsomal membrane. Newly synthesized tubulin which has been extracted from microsomal membranes in 0.5% Nonidet P-40, coassembles and disassembles with carrier microtubule protein. The insertion of newly synthesized tubulin into endoplasmic reticulum membrane may be the first step in the incorporation of tubulin into the plasma membrane.

Association of Newly Synthesized Tubulin with Brain Microsomal Membranes

Large amounts of a nerofilament-enriched fraction may be prepared from spinal cord homogenates by a simple, three-step procedure. This involves flotation of filament-containing axon fragments, extraction with Triton X-100, and washing by sedimentation through a sucrose density gradient. The material obtained by this procedure includes both large mats of individual 10-nm filaments and tightly packed bundles of filaments. SDS-gel electrophoresis of these fractions indicates that the fractions are formed of four polypeptides: the three which are generally considered to form neurofilaments (P200, P150, and P68) and another, with a molecular weight of about 50,000 daltons (P50), which is thought to be derived from fibrous astrocytes. Analysis of these filament fractions on two-dimensional gels indicate heterogeneity among each of the different molecular weight classes. The largest polypeptide of neurofilaments, P200, focuses at several spots in the pH gradient. P68 and P150 are more acidic: each appears as a pair of overlapping spots. P50 resolves into a complex of spots of about the same molecular weight but with different isoelectric points. Heterogeneity is not unique to these filament polypeptides but appears to be a characteristic of all fibrous proteins of the nervous system.

Heterogeneity of intermediate filament proteins from rabbit spinal cord

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