Krister Kristensson

Fatty acid composition of brain phospholipids in aging and in Alzheimer’s disease

The two major phospholipid classes, namely, phosphatidylethanolamines (PE) and phosphatidylcholines (PC), were studied in four different regions of human brain,i.e., in frontal gray matter, frontal white matter, hippocampus and in pons. The fatty acid (FA) compositions of these phospholipids were found to be specific for the different regions. PC contains mostly saturated and 18∶1 FA, while PE is rich in polyunsaturated FA. Aging has no influence on the FA compositions, while in Alzheimer’s disease (AD) PE is modified in all four regions, particularly in frontal gray matter and in hippocampus. The abundance of the major monounsaturated FA of PE, 18∶1, is not significantly altered in Alzheimer’s disease, but there is a substantial increase in the relative amounts of the saturated components 14∶0, 16∶0 and 18∶0. This is paralleled by a decrease in the polyunsaturated FA 20∶4, 22∶4 and 22∶6. It is not clear whether the changes observed are specific for AD. Changes in saturated/polyunsaturated FA ratio are likely to influence cellular function, which in turn may cause certain neural deficiencies. The findings do not support the hypothesis that AD reflects an accelerated aging process.

Axonal uptake and retrograde transport of exogenous proteins in the hypoglossal nerve

Abstract Exogenous proteins (albumin labelled with Evans blue (EBA) and horseradish peroxidase) were injected into the tongue of various laboratory animals (rats, rabbits, mice and guinea pigs). At various time intervals thereafter the hypoglossal nuclei were examined with regard to the cytological localization of the tracers. In the hypoglossal neurones red fluorescent cytoplasmic were seen 10 h after injection of EBA into adult rats and rabbits indicating the presence of protein tracer. Peroxidase also accumulated in these neurones of suckling and adult mice and rats. The neuronal uptake of the protein tracers was blocked by crush injuries to the hypoglossal nerve and by arrest of blood circulation. Our results show that the hypoglossal neurones have the capacity to accumulate exogenous proteins after peripheral injection. This process must be a consequence of a fast retrograde axonal transport. As shown in previous studies, a similar transport also occurs in the peripheral motor neurones of the spinal cord in suckling mice. This phenomenon therefore exists in different species, ages and kinds of nerve.

Lipid Compositions of Different Regions of the Human Brain During Aging

The neutral and phospholipid compositions of various regions of the human brain were analyzed using autopsy material covering the life period between 33 and 92 years of age. The protein content was also measured and, on a weight basis, this content is unchanged in the cerebellum, pons, and medulla oblongata, whereas in the 90‐year‐old group it decreases in the hippocampus, gray matter, and nucleus caudatus. In white matter, the protein content decreases continuously with age. The phospholipid composition is characteristic of the region investigated, but remains unchanged during aging. The total phospholipid content exhibits only a 5–10% decrease in the oldest age group. The content of dolichol and its polyisoprenoid pattern are also characteristic of the region analyzed. Between 33 and 92 years of age, the amount of dolichol in all portions of the brain increases three‐to fourfold, but the isoprenoid pattern remains constant. The level of dolichyl‐P varies between different regions, but only a moderate increase is seen with age. Ubiquinone content is highest in the nucleus caudatus, gray matter, and hippocampus, and in all areas this content is decreased to a great extent in the oldest age groups. All regions of the human brain are rich in cholesterol, but alterations in the amount of this lipid are highly variable during aging, ranging from no change to a 40% decrease.

Spread of herpes simplex virus in peripheral nerves

SummarySuckling mice were inoculated intradermally with herpes simplex virus into the sole of the hind foot. Titrations for infective virus from different levels of the sciatic nerve, dorsal ganglia, and spinal cord showed that virus was already present in the spinal cord two days after inoculation, and before virus could be recovered from the examined levels of the sciatic nerve. Ligatures, freezing, and local treatment with colchicine of the sciatic nerve could prevent the spread of infection. The ultrastructural features of nerves soaked with mitosis inhibitors are described. Extensive changes with ultimate collapse of axons and disintegration of myelin sheaths were found, while the Schwann cells showed no obvious degenerative changes and the endoneurial spaces were wide. It is considered that the infectious agent travels inside the axons to the CNS, and that a spread of virus in endoneurial spaces or by propagation in Schwann cells, as recently has been suggested, is of minor importance. The study seems to provide evidence that inside the axons a transport of materials directed disto-proximally all the way to the nerve cell body exists.ZusammenfassungSaugmäuse wurden intradermal in die Sohle des Hinterbeines mit Herpes simplex-Virus inoculiert. Titrationen auf das infektiöse Virus in verschiedenen Höhen des N. ischiadicus, der Dorsalganglien und des Rückenmarks zeigten, daß das Virus im Rückenmark schon 2 Tage nach der Inoculation, und ehe es in verschiedenen Abschnitten des N. ischiadicus nachgewiesen werden konnte, vorhanden war. Ligaturen, Durchfrieren und örtliche Behandlung des N. ischiadicus mit Colchicin konnte die Infektionsausbreitung verhindern. Die ultrastrukturellen Veränderungen der mit Mitosehemmern durchtränkten Nerven werden beschrieben. Es fanden sich starke Veränderungen der Axone mit schließlichem Kollaps sowie Desintegration der Markscheiden, während die Schwann-Zellen keine auffälligen degenerativen Veränderungen zeigten und die Endoneuralräume weit waren. Es wird angenommen, daß das infektiöse Agens innerhalb der Axone zum ZNS wandert und daß eine Ausbreitung des Virus, in den Endoneuralräumen oder in den Schwann-Zellen, wie es kürzlich vermutet worden war, von geringerer Bedeutung ist. Die Studie scheint den Nachweis zu erbringen, daß ein distoproximaler Materialtransport innerhalb der Axone bis zum Nervenzellkörper stattfindet.

Lipid composition in different regions of the brain in Alzheimer's disease/senile dementia of Alzheimer's type

Abstract: The lipid compositions of 10 different brain regions from patients affected by Alzheimers disease/senile dementia of Alzheimers type were analyzed. The total phospholipid amount decreased somewhat in nucleus caudatus and in white matter. The cortical areas that are morphologically affected by Alzheimers disease, i.e., frontal and temporal cortex and the hippocampus, showed elevated contents of lipid solvent‐extractable phosphatidylinositol. Sphingomyelin content was decreased in regions rich in myelin. There was a 20–50% decrease in dolichol amount in all investigated parts of the brain, but no change was seen in the polyisoprenoid pattern. Levels of α‐unsaturated polyprenes were decreased in Alzheimer brains. Dolichyl‐phosphate content increased in most regions, up to 100%. In both control and Alzheimer tissue almost all of the dolichyl‐phosphate was covalently bound, apparently through glycosylation. Cholesterol amounts were highly variable but mostly unchanged, whereas ubiquinone concentrations increased by 30–100% in most regions in brains affected by Alzheimers disease. These results demonstrate that both phospholipids and neutral lipids are modified in brains affected by Alzheimers disease/senile dementia of Alzheimers type.

Retrograde transport of horseradish peroxidase in transected axons. 3. Entry into injured axons and subsequent localization in perikaryon

Horseradish peroxidase (HRP) applied to crushed mouse sciatic nerves diffused through the damaged perineurium into the endoneurium. In the injured area, HRP passed into damaged myelinated and unmyelinated axons forming columns of reaction product, which extended for several millimeters proximally to the lesion. Ultrastructurally, HRP adhered to the inner surface of the axoplasm and to the surfaces of neurotubules and neurofilaments in such columns. At more proximal levels axons contained HRP in vesicular and tubular organelles and, later, nerve cell bodies of the corresponding spinal ganglia showed HRP, accumulation in cytoplasmic vesicles, cup-shaped bodies, multivesicular bodies and tubules of agranular endoplasmic reticulum. Markedly less HRP reached neurons in the spinal ganglia when applied to the nerve 30 or 60 min after the crush. After such time intervals solid HRP containing axons were also less frequently observed. Conceivably, HRP enters crushed axons momentarily after a crush as an injured cell reaction. Subsequently it is incorporated into organelles higher up in the axons, from where retrograde transport to the perikaryon will fellow. This phenomenon of a sudden non-specific influx of exogenous macromolecules into axotomized neurons and their subsequent transport to the perikaryon might be relevant for development of certain biochemical and morphological responses, e.g. lysosomal alterations, of the neuron to an axonal injury.

Retrograde transport of horseradish peroxidase in transected axons. 1. Time relationships between transport and induction of chromatolysis

Abstract Horseradish peroxidase applied to the traumatized area of a crushed or a cut facial nerve of mice accumulated in the neuronal perikarya of the facial nucleus 6 h after the application. This accumulation is probably the result of uptake of the protein tracer in axons proximal to the trauma, followed by intraaxonal transport in the retrograde direction. The protein tracer arrived in the perikarya prior to the earliest described response of these neurons to axonal injury. In this respect different hypotheses involving a disturbed retrograde transport of macromolecules for eliciting chromatolysis of peripheral neurons following injury to their axons are reviewed.

CD8 is critically involved in lymphocyte activation by a T. brucei brucei-released molecule

T. brucei brucei released a lymphocyte triggering factor (TLTF), which triggered purified CD8+, but not CD4+, T cells to interferon gamma (IFN-gamma) mRNA expression and secretion and to [3H]thymidine incorporation. TLTF also induced mRNA for transforming growth factor beta, but not for interleukin-4. The action of this TLTF on mononuclear cell (MNC) cultures was blocked by anti-CD8 antibodies and by soluble CD8. MNCs from a mutant mouse strain lacking CD8 expression were not triggered by TLTF. IFN-gamma provides a growth stimulus for T. brucei brucei, and infected CD8- mice had much lower parasitemia and survived longer than CD8+ mice. The host-parasite interaction in experimental African trypanosomiasis thus involves parasite release of TLTF, which by binding to CD8 triggers CD8+ cells to produce the parasite growth-promoting cytokine IFN-gamma.

Uptake and Transport of Herpes Simplex Virus in Neurites of Rat Dorsal Root Ganglia Cells in Culture

Attachment and neuritic transport of herpes simplex virus (HSV) type 1 (McIntyre) were studied in a cell culture system with dissociated cells of rat dorsal root ganglia. The two-chamber cell culture system containing a diffusion barrier penetrated by neurites of cultured sensory neurons permitted infection of neurites extending outside the diffusion barrier without exposure of the neuronal cell soma. HSV adsorbed to neuritic extensions and reached the neuronal soma within 1.5 h post-inoculation. Neuritic uptake and transport of HSV were inhibited in the presence of cytochalasin B. Internalization of virus in neurites was preceded by attachment of virus to the neurite plasma membrane. Neurites transported viral nucleocapsids (NC) through the diffusion barrier of the cultures. Destruction of the neuritic extensions before or shortly after peripheral virus inoculation blocked spread of infection to the cell soma. No infection was established when neuritic extensions were exposed to viral NC and NC were then not observed inside the neurite plasma membrane. Virus produced in neurons, when HSV was inoculated into the inner culture chamber containing the neuronal cell bodies, was transported as enveloped virus in cytoplasmic vesicles from the neuronal cell body towards the periphery. Schwann cells were infected by viropexis. Shortly after infection virions were observed in vacuoles of the cytoplasm.

Neuron to neuron transmission of herpes simplex virus ☆: Transport of virus from skin to brainstem nuclei

Herpes simplex virus (HSV) injection into the snout of mice was followed by the appearance of HSV antigen in neurons in trigeminal ganglia, main sensory and spinal tract trigeminal nuclei, reticular formation including raphe nuclei and locus ceruleus on both sides. The findings indicate that HSV spreads via axons, passes through a series of neurons and in this way can reach vital nuclei in the brainstem including monoaminergic neurons from the primary replication area in the lip.