Biochemical dysfunction and memory loss: the case of Alzheimer's dementia

Among the different types of cognitive impairment that appear with increasing age, Alzheimer's disease (AD) is rated as the most frequent. Despite intensive research, key questions concerning AD aetiology remain elusive, but it appears that many biochemical events crucial for neuronal communication and synaptic plasticity fail during the course of the disease. The aim of this review is therefore to provide an overview of intracellular cascades involved in AD pathology. For almost all factors. it is a matter of controversy whether their contribution should be considered to be cause or effect. However, intracellular signalling may be crucial as it is in learning and memory mechanisms and malfunction of biochemical pathways may be a common denominator in neurodegenerative processes, thus providing new venues for treatment and therapeutic strategies.     

Cholinergic, monoaminergic and glutamatergic changes following perinatal asphyxia in the rat

Perinatal asphyxia (PA) is considered to lead to a variety of brain disorders including spasticity, epilepsy, mental retardation, and minimal brain disorder syndromes and may form the basis for psychiatric and neurodegenerative diseases later in life. We examined markers for neuronal transmission involved in the pathomechanisms of PA and candidates as mediators for long-term sequelae. We tested tyrosine hydroxylase (TH) and the vesicular monoamine transporter (VMAT) representing the monoaminergic system, the vesicular acetylcholine transporter (VAChT), and the excitatory amino acid carrier 1 (EAAC1), a neuronal subtype of the glutamate transporter, using immunohistochemistry on brain sections of rats subjected to graded PA. Three months following the asphyxiant insult immunoreactive (IR)-TH was decreased in striatum, hippocampus, thalamus, frontal cortex, and cerebellum; IR-VMAT was increased, and IR-VAChT was decreased in striatum. IR-EAAC1 glutamate transporter was increased in frontal cortex. The cholinergic, monoaminergic, and glutamatergic changes, still observed 3 months after the asphyxiant insult, may reflect their involvement in the pathomechanisms of PA and indicate mechanisms leading to long-term complications of PA. The variable consequences on the individual markers in several brain regions may be explained by specific susceptibility of cholinergic, monoaminergic, and glutamatergic neurons to the asphyxiant insult. Received 16 March 1999; received after revision 20 May 1999; accepted 8 July 1999     

Hemoglobin causes both endothelium-dependent and endothelium-independent contraction of the pig coronary arteries, independently of an inhibition of EDRF effects

Hemoglobin is widely used as an inhibitor of EDRF effects. Hemoglobin contracts pig coronary arteries in vitro. However, during this contraction, effects of substance P and bradykinin which act via the EDRF are not inhibited. This means that the hemoglobin contraction is not caused by inhibition of the EDRF. This contraction is caused by a substance released from the endothelium, and by eicosano?ds released from the smooth muscles.     

Cerebral ischemia revisited: New insights as revealed using in vitro brain slice preparations

Summary The elucidation of the pathophysiological mechanisms of cerebral ischemia/hypoxia dictates the use of experimental models which mimic this disabling brain condition. In vivo experimental models have been available for many decades and are responsible for the bulk of, though incomplete, knowledge we have about these mechanisms. Since study in isolation of each postulated mechanism is impossible in vivo, the need for an in vitro experimental model has intensified in recent years. Consequently, rat and guinea pig hippocampal slice preparations have emerged as the models of choice. This review attempts to highlight some of the results obtained using brain slices in the study of cerebral ischemia/hypoxia and compare them to those obtained in vivo. Both the biochemical and the physiological correlates of energy metabolism, ion homeostasis, neurotransmission and neuromodulation of this brain condition are reviewed. The agreements, and especially the disagreements, between the in vivo and in vitro findings are emphasized. Details are given of the possible roles of both lactic acid, Ca²⁺ and excitotoxins in the neuronal damage inflicted by cerebral ischemia/hypoxia. Recent attempts to protect brain slices against experimental cerebral ischemic/hypoxic damage are also reviewed here briefly.     

Plasmid-related anaerobic autotrophy of the novel archaebacterium Sulfolobus ambivalens

Three different species of the genus Sulfolobus, S. acidocaldarius, S. solfataricus (= Caldariella) and S. brierleyi, have been distinguished by the conditions required for optimal growth, by the component patterns of their DNA-dependent RNA polymerases and by DNA sequence data. Many isolates of these species are able to grow chemolithoautotrophically using CO2 as the sole carbon source and the oxidation of S(0) with O2 yielding sulphuric acid, as the energy source, though a few others grow only heterotrophically. We show here that a strain of a novel Sulfolobus species, S. ambivalens, is alternatively able to live by an anaerobic mode of chemolithoautotrophy, also using CO2 as the sole carbon source, but using reduction of S(0) with H2, yielding H2S as the energy source. This mode of growth is correlated with the amplification of a plasmid, pSL10.     

Heritability of locomotor performance and its correlates in a natural population

Summary Locomotor capacities and their physiological bases are thought to be of considerable selective importance in natural populations. Within this functional complex, organismal performance traits (e.g., speed, stamina) are expected to be of more direct selective importance than their suborganismal determinants (e.g., heart size). Quantitative genetics theory predicts that traits of greater selective importance should generally have lower heritabilities at equilibrium. Contrary to these expectations, we report that organismal performance traits had the highest heritabilities in a natural population of garter snakes.     

Role of myelin P0 protein as a homophilic adhesion molecule.

Peripheral nervous system myelin is an extension of the Schwann cell's plasma membrane that tightly enwraps axons in many layers and permits nerve impulses to be rapidly conducted. It is not known how these multiple membrane layers are held together in this compact form. Here we present evidence supporting the hypothesis that the extracellular leaflets of myelin are held together by the most abundant protein of myelin of the peripheral nervous system, P0, by homophilic interaction of its extracellular domains. Transfected Chinese hamster ovary cells expressing P0 protein adhere to each other in suspension, to form large aggregates, whereas cells that are identical but which do not express P0 do not. We also show that this aggregation is mediated by homophilic binding between P0-expressing cells and that the apposing plasma membranes of these cells specifically form desmosomes, whereas control transfected cells do not. As the only difference between the two cell populations is the expression of P0, this protein is apparently responsible for the changes in morphology and adhesion in the cells that express it. The idea that P0 is a homophilic adhesion molecule is supported by its inclusion in the immunoglobulin supergene family, all members of which are involved in recognition and/or adhesion.     

Mitogens trigger a calcium-independent signal for proliferation in phorbol-ester-treated lymphocytes

The activation of T lymphocytes by mitogens requires at least two signals; the first, delivered to T cells by a mitogen in conjunction with accessory cells (monocytes/macrophages), leads to the generation of the second signal, interleukin-2 (IL-2). The first signal also induces the expression of IL-2 receptors on the surface of a subpopulation of T cells; binding of IL-2 to its receptor then initiates a cascade of events culminating in DNA synthesis by these cells. Certain compounds act synergistically with mitogens in promoting T-cell proliferation by substituting for the activities of interacting cells or their products. For example, the phorbol ester 12-O-tetradecanoyl phorbol 13-acetate (TPA) has been shown to restore the ability of macrophage-depleted T-cell populations to respond to mitogenic lectins. Transmembrane fluxes of calcium, leading to increased free cytosolic calcium concentrations ([Ca2+]), have been demonstrated following mitogen binding to lymphocytes and have been implicated in the initiation of cell proliferation. We show here that the effect of TPA on lymphocyte proliferation occurs in the absence of extracellular Ca2+ or detectable changes in [Ca2+]i, but only in the presence of mitogens. This suggests that in cells which have been incubated with the phorbol ester, mitogens can induce proliferation by a calcium-independent signal.     

Novel oscillations in cell suspensions ofDictyostelium discoideum

Summary With a light-scattering technique, two novel rhythms were discovered in cell suspensions ofDictyostelium discoideum. One is a damped oscillation with a period of 2 to 2.5 min (at 23°C) induced by folate in EDTA-dissociated undifferentiated cells. The other is a sinusoidal oscillation with a period of about 12 min occasionally observed with late differentiated cells. Obviously, the repertoire of rhythms of this simple eukaryotic organism is larger than previously assumed.