The neurochemistry of Alzheimer's disease

Our knowledge of the neurochemical pathology of AD has increased immensely the last years. Although it is now clear that mutations in the APP gene can cause some rare hereditary forms of AD, and that ApoE4 is a prominent risk factor for AD, we at present know little about the underlying cause of AD in the general population and the biochemical mechanisms by which the apolipoprotein E4 isoform affects AD pathogenesis. It is hoped that the near future will see a resolution of the current controversies in AD research, including: 1) whether APP mutations cause Alzheimer's disease by affecting Aβ deposition or the function of APP itself; 2) whether abnormal phosphorylation of tau is a central pathogenetic event, or whether it occurs as epiphenomena that reflect general neurodegeneration in a variety of disease processes; 3) Whether Aβ deposition in the brain is the central event in AD or whether it occurs as epiphenomena in a variety of brain disorders such as head trauma; and 4) whether altered tau phosphorylation occurs secondary to Aβ deposition or vice versa, and what the link is (if any) between the two processes.     

Investigation of the anti-complement agents, FUT-175 and K76COOH, in discordant xenotransplantation

Abstract: We examined whether hyperacute rejection (HAR) of a discordant xenograft in a nonhuman primate model could be inhibited by the anticomplement agents, FUT-175 (FUT) and K76COOH (K76). The inhibitory effect of FUT and K76 on baboon sera was studied in vitro by i) complement-mediated hemolysis of sheep erythrocytes (by measuring serum CH50) and ii) cytotoxicity to cultured pig kidney (PK15) cells. The in vivo administration of FUT (at 0.2–25 mg/kg/h i.v. continuously) and K76 (50 mg/kg i.v. bolus) allowed evaluation of the serum levels of these drugs. Both FUT and K76 inhibited serum CH50 in a concentration-dependent manner. An enhanced effect was obtained by combining K76 with FUT therapy. High concentrations of FUT (>10^-4 M) and K76 (>10³ μxg/ml) were necessary to suppress serum CH50 to <5% of the normal level. However, PK15 cytotoxicity remained at >50% in the presence of i) 10^-4 M of FUT, ii) 10³ μg/ml of K76, and iii) 10^-6 M of FUT + 10³ μg/ml of K76. Pig heart transplantation (HTX) was performed in two baboons receiving FUT (1 mg/kg/h i.v. continuously) and K76 (at 200 mg/kg ×1 or 400 mg/kg + 200 mg/kg × 2 i.v, respectively). Cytotoxicity of the serum to PK15 cells at the time of HTX showed 39% and 1% cell death, respectively, in these two baboons, and the CH50 level was 1% (of control level) and 0%, respectively. Graft survival was 4.5 hours and 10 hours (with death of the baboon), respectively (compared with a mean of 29 minutes in control experiments). Both excised grafts showed typical features of hyperacute rejection. Immunopathological studies revealed deposition of C1q, C3d, C6, properdin, and Factor B, demonstrating that complement activation was not fully inhibited by FUT and K76. We conclude that i) FUT and K76 are indeed potent complement inhibitors, ii) the dosages of FUT and K76 necessary to suppress complement-mediated injury cannot be extrapolated from previously reported data obtained from serum CH50 levels, and iii) higher (possibly toxic) dosages will be required to inhibit complement activation completely. It seems unlikely that HAR will be prevented by these drugs alone, although they may be beneficial when combined with other forms of therapy.     

Proteolytic Processing Mechanisms in the Biosynthesis of Neuroendocrine Peptides: The Subtilisin-like Proprotein Convertases

The recent discovery of a novel family of precursor processing endoproteases has greatly accelerated progress in understanding the complex mechanisms underlying the maturation of prohormones, neuropeptides, and many other precursor-derived proteins. At least six members of this family have been found thus far in mammalian species, several having alternatively spliced isoforms, and related enzymes have been identified in many invertebrates, including molluscs, insects, nematodes, and coelenterates. The proprotein convertases are all dependent on calcium for activity and all possess highly conserved subtilisin-like domains with the characteristic catalytic triad of this serine protease (ordered Asp, His, and Ser along the polypeptide chain). Two members of this family, PC2(SPC2) and PC1/PC3(SPC3), appear to play a preeminent role in neuroendocrine precursor processing. Both convertases are expressed only in the brain and in the extended neuroendocrine system, while another important family member—furin/PACE (SPC1)—is expressed more ubiquitously, in almost all tissues, and at high levels in liver. SPC2 and SPC3 exhibit acidic pH optima and other properties which enhance their activity in the acidic, calcium-enriched environment of the dense-core secretory granules of the regulated pathway in neuroendocrine cells, while furin has a neutral pH optimum and is localized predominantly to the trans Golgi network where it is retained by a C-terminal transmembrane domain. Furin processes a wide variety of precursors in the constitutive pathway, such as those of growth factors, receptors, coagulation factors, and viral glycoproteins. Recent findings on the processing of proopiomelanocortin, proinsulin, proglucagon, and several other neuroendocrine precursors by SPC2 and SPC3 are discussed, along with information on the structure, properties, evolution, developmental expression, and regulation or the convertases. An inherited defect in the fat/fat mouse which affects the processing of proinsulin, and probably also many other prohormones, due to a point mutation in carboxypeptidase E has recently been identified and has begun to provide new insights into the functional integration of the individual processing steps.     

Conditions of Alzheimer-type dementia in the old-old and oldest-old patients with special reference to extreme conditions of brain aging

A neuropathological study on 1540 consecutive autopsy brains ranging from 60 to 107 years of age revealed the following points. (1) Of the of the demented cases of the plaque-predominant type, 93% were complicated with multiple tiny cortical infarcts. They showed a tendency for dementia to develop before or after the appearance or worsening of a systemic disorder such as cardiovascular disease, respiratory infection and cancer. However, there was no case showing Alzheimer-type dementia (ATD). (2) The plaque-predominant type might be an extreme condition of brain aging in terms of senile plaques (SP). It is likely that although the pathological appearance of SP alone is not responsible for dementia, its coexistence with multiple cortical infarcts could be the cause of dementia. Therefore, this type should be distinguished from ATD. (3) Primary hippocampal degeneration could also be an extreme condition of brain aging in terms of neurofibrillary tangles. This condition was different pathologically from the hippocampal lesion in ATD. (4) Several characteristics of old-old and oldest-old patients were clarified.     

The role of Na+/K+ ATPase activity during low flow ischemia in preventing myocardial injury: A 31P, 23Na and 87Rb NMR spectroscopic study

An increase in intracellular Na⁺ during ischaemia has been associated with myocardial injury. In this study, we determined whether inhibition of Na⁺/K⁺ ATPase activity contributes to this increase and whether Na⁺/K⁺ ATPase activity can be maintained by provision of glucose to perfused rat hearts during low flow, 0.5 ml/min, ischemia. We used ³¹P NMR spectroscopy to determine changes in myocardial energetics and intracellular and extracellular volumes. ²³Na NMR spectroscopy, with DyTTHA^3- present as a shift reagent, was used to measure changes in intracellular Na⁺ and ⁸⁷Rb NMR spectroscopy was used to estimate Na⁺/K⁺ ATPase activity from Rb⁺ influx rates, Rb⁺ being an NMR-sensitive congener of K⁺. In hearts provided with 11 mM glucose throughout ischemia, glycolysis continued and ATP was twofold higher than in hearts without glucose. In the glucose-hearts, Rb⁺ influx rate was threefold higher, intracellular Na⁺ was fivefold lower at the end of ischemia and functional recovery during reperfusion was twofold higher. We propose that continuation of glycolysis throughout low flow ischemia allowed maintenance of sufficient Na⁺/K⁺ ATPase activity to prevent the increase in intracellular Na⁺ that would otherwise have led to myocardial injury.     

The Drosophila Mutant tetanic Interacts with a Gene Complex Including the Structural Locus of K+ Channels and Shows Altered Dephosphorylation and Learning

The tetanic (tta; X.-52.6) mutation has been isolated on the basis of its sensitivity to extradoses of the normal Shaker gene complex (ShC) where the K+ channel la is encoded. The mutant shows up to threefold elevation of the membrane bound protein phosphatase type 1 (PP1) activity in body extracts, probably due to reduced levels of the PP1 specific inhibitor 2 (I-2). By contrast, PP1 activity in the head is only half of the normal value. In addition, tta fails to perform normally in a negative reinforcement olfactory paradigm. The functional relationships between phosphorylation, K+ currents, phosphatase activity and modulation of synaptic activity during learning and memory are discussed in the light of their possible genetic links.     

新生儿G6PD缺陷病和晚发性维生素K缺乏症的特点与预防

目的 探讨新生儿C6PD缺陷病和晚发性维生素K缺乏症的危害与预防措施。方法 回顾分析1995-2000年儿内科住院的1周-2月(不含2月)的婴儿3104例次，其中病死56例。结果 1周-2月的小婴儿占住院患儿的19．34％，其中新生儿G6PD缺陷病239例，占7．70％；晚发性维生素K缺乏症92例，占2．96％。死因的第2、3位分别是晚发性维生素K缺乏症(13例，占23．21％)和新生儿C6PD缺陷病(12例，占21．43％)，两者的病死率分别为14．13％和5．02％，极显著高于(x^2＝17．59，P＜0．01)或相近于(x^2＝0．88，P＞0．05)肺炎的3．57％。新生儿G6PD缺陷病合并感染占38．49％、低氧血症占23．35％、低血糖占19．25％、酸中毒占15．90％，继发胆红素脑病占13．81％。晚发性维生素K缺乏症出现抽搐占90．22％、胃肠、注射部位出血占60．89％；CT证实颅内出血占98．91％。结论 1周-2月的小婴儿约占住院患儿的两成，新生儿G6PD缺陷病和晚发性维生素K缺乏症的病死率均很高，两者是除肺炎外最主要的死因。提议制定并推广预防这2种疾病的常规措施，并参照国内外相应的现状拟出其具体内容。     

Serum 27E10 antigen: a new potential marker for staging HIV disease.

MRP8 and MRP14 are myeloic related proteins expressed by most circulating and emigrated neutrophils and monocytes. Their composite molecule MRP8/14 (27E10 antigen) was shown to exhibit striking antimicrobial properties. The aim of the present study was to assess the value of MRPs as markers for detection of the different stages of HIV infection (Centres for Disease Control and Prevention, 1993). By employing the ELISA technique we measured serum concentrations of these proteins in samples from 122 HIV patients at the various stages of disease, and the results were compared with those for healthy controls. Serum levels of the heterodimeric molecule 27E10 were significantly increased (P < 0.001) in patients with CDC stages II and III, with the highest levels being in patients with stage III and acute ongoing opportunistic infections. For the single component MRP14, significantly raised levels (P < 0.05) were only found in HIV stage III individuals with acute clinical events. Similar associations were not found for MRP8 alone. Increase was not related to CD4+ cell count. There was a significant correlation between 27E10 antigen serum concentrations and levels of neopterin in patients with HIV stages II and III without acute concurrent illness. Patients being treated with Zidovudine showed no statistically significant variation in levels of 27E10 and its single components MRP8 and MRP14 compared with untreated patients. These findings suggest that elevation of MRP14 levels occurs in HIV+ individuals at later stages post-HIV infection, after the onset of opportunistic infections. 27E10 antigen is concluded to be a potential marker for the different stages of HIV disease.     

Homozygous microdeletion of chromosome 4q11-q12 causes severe limb-girdle muscular dystrophy type 2E with joint hyperlaxity and contractures

Microdeletion syndromes are commonly transmitted as dominant traits and are frequently associated with variably expressed pleiotropic phenotypes. Nonlethal homozygous microdeletions, on the other hand, are very rare. Here, we delineate the fifth and so far largest homozygous microdeletion in nonmalignancies of approximately 400 kb on chromosome 4q11-q12 in a large consanguineous East-Anatolian family with six affected patients. The deleted region contains the beta-sarcoglycan gene (SGCB), the predicted gene SPATA18 (spermatogenesis associated 18 homolog) and several expressed sequence tags. Patients presented with a severe and progressive Duchenne-like muscular dystrophy phenotype, a combination of hyperlaxity and joint contractures, chest pain, palpitations, and dyspnea.