GGA1 acts as a spatial switch altering amyloid precursor protein trafficking and processing

The beta-amyloid (Abeta) precursor protein (APP) is cleaved sequentially by beta-site of APP-cleaving enzyme (BACE) and gamma-secretase to release the Abeta peptides that accumulate in plaques in Alzheimer's disease (AD). GGA1, a member of the Golgi-localized gamma-ear-containing ARF-binding (GGA) protein family, interacts with BACE and influences its subcellular distribution. We now report that overexpression of GGA1 in cells increased the APP C-terminal fragment resulting from beta-cleavage but surprisingly reduced Abeta. GGA1 confined APP to the Golgi, in which fluorescence resonance energy transfer analyses suggest that the proteins come into close proximity. GGA1 blunted only APP but not notch intracellular domain release. These results suggest that GGA1 prevented APP beta-cleavage products from becoming substrates for gamma-secretase. Direct binding of GGA1 to BACE was not required for these effects, but the integrity of the GAT (GGA1 and TOM) domain of GGA1 was. GGA1 may act as a specific spatial switch influencing APP trafficking and processing, so that APP-GGA1 interactions may have pathophysiological relevance in AD.     

A case of malignant fibrous histiocytoma with metastatic brain tumors after tumorgenic embolism]

A 61-year-old man had been treated for malignant fibrous histiocytoma with the pulmonary and the lymph node metastasis in the department of orthopedics in our hospital. He was admitted to our department because of an acute onset of conscious disturbance and non-fluent aphasia. Diffusion-weighted imaging (DWI) showed high signal intensity areas in the bilateral cerebella, thalami and posterior lobes. T2WI did not show any mass effects. Enhanced CT did not reveal any enhanced lesion. He was diagnosed as having cerebral embolism, and his conscious disturbance was improved after medication. Eight weeks later, he presented dysphagia, dysarthria, and ataxia in his extremities. DWI showed multiple lesions of low signal intensity located at the identical place where had showed high signal intensity in the initial DWI. T2WI showed high signal intensity area with mass effect. It was indicated that cerebral metastasis might grow after tumorgenic embolism. This is a rare case that tumor emboluses were developed to the metastatic brain tumors.     

The synthesis and localization of alternatively spliced fibronectin EIIIB in resting and thrombin-treated megakaryocytes

There are several species of alternatively spliced fibronectin (FN). One of these, FN EIIIB, is primarily present in embryonic and in proliferating and migrating cells and is believed to be important for cell maturation. We have studied the synthesis, localization, and secretion of this FN isoform in isolated guinea pig megakaryocytes, nonmegakaryocytic bone marrow cells, and platelets. There was 7.5 times more general FN in megakaryocytes than in nonmegakaryocytic cells based on the analysis of equivalent amounts of protein. FN EIIIB was detected by Western blotting in megakaryocytes but not in nonmegakaryocytic cells present in bone marrow. Neither megakaryocytes nor platelets secreted FN EIIIB, while megakaryocytes secreted 25.3% +/- 4.6% general FN and platelets secreted about 61% general FN in response to thrombin. Analysis of immunostained cells by confocal microscopy revealed that FN EIIIB had been redistributed to the surface of megakaryocytes in response to thrombin. Synthesis was studied by metabolic labeling, and megakaryocytes were shown to synthesize FN and FN EIIIB. Thus, megakaryocytes and platelets are among a small number of adult cells and tissues that synthesize and contain FN EIIIB. The expression of FN EIIIB on the megakaryocyte surface may influence migration and maturation.     

Isolated angitis of the central nervous system--case report and review

Isolated angitis of the central nervous system (IACNS) is rare condition with inflammation limited to vessels supplying the brain. This IACNS has been a poorly characterized and infrequently reported illness since it was first described as a separate entity in 1959. However, a patient with IACNS has not been reported in Japan. A patient, 39-year old-male, with IACNS limited to small and middle vessels is described. Recurrent, transient consciousness disturbances, focal myoclonus, papilloedema and temporal lobe epilepsy were observed during disease course. CSF finding of this patient showed lymphocytosis with marked increased protein. Carotid and vertebral angiogram showed irregular luminal outline in branches of all arteries. The most specific finding is that of alternating areas of focal stenosis and ectasia giving a "sausage" pattern. These characteristic findings showed in the branch of external carotid arteries. There was no evidence of systemic vasculitis by systemic angiography. Biopsy of temporal artery showed lymphocyte infiltration, fibrinoid necrosis without giant cell and granuloma. Formation of A-V malformation in the branch of external carotid artery was also observed. This histopathological finding was compatible with necrotizing angitis, not granulomatous angitis. Isolated angitis of the central nervous system was diagnosed. In spite of his administration of corticosteroid, cerebrospinal fluid abnormalities has not responded markedly. Abnormal findings of carotid and vertebral angiogram also has not changed. After 7 years from his onset, his neurologic signs and symptoms were well controlled with administration of anti-epileptic drugs.     

Association of the insertion/deletion polymorphism of the angiotensin I-converting enzyme gene in patients of migraine with aura

Recently, several angiotensin I-converting enzyme (ACE) inhibitors and an angiotensin II receptor blocker were demonstrated to have a clinically important prophylactic effect in migraine. ACE is one of the key enzymes in the rennin-angiotensin-aldosterone system, which modulates vascular tension and blood pressure. In humans, serum ACE levels are strongly genetically determined. Individuals who were homozygous for the deletion (D) allele showed increased ACE activity levels. To investigate the role of ACE polymorphism in headache, we analyzed the ACE insertion (I)/deletion (D) genotypes of 54 patients suffering from migraine with aura (MwA), 122 from migraine without aura, 78 from tension-type headache (TH), and 248 non-headache healthy controls. The ACE D allele were significantly more frequent in the MwA than controls (p<0.01). The incidence of the D/D genotype in MwA (25.9%) was significantly higher than that in controls (12.5%; p<0.01; odds ratio=5.26, 95% confidence interval: 1.69-16.34, adjusted for age and gender). No differences in the remaining groups were found. Our results support the conclusion that the D allele and the D/D genotype in the ACE gene is a genetic risk factor for Japanese MwA. There seems to be a possible relationship between ACE activity and the pathogenesis of migraine.     

Mostly separate distributions of CLAC- versus Abeta40- or thioflavin S-reactivities in senile plaques reveal two distinct subpopulations of beta-amyloid deposits

Collagenous Alzheimer amyloid plaque component (CLAC) is a unique non-Abeta amyloid component of senile plaques (SP) derived from a transmembrane collagen termed CLAC-precursor. Here we characterize the chronological and spatial relationship of CLAC with other features of SP amyloid in the brains of patients with Alzheimer's disease (AD), Down syndrome (DS), and of PSAPP transgenic mice. In AD and DS cerebral cortex, CLAC invariably colocalized with Abeta42 but often lacked Abeta40- or thioflavin S (thioS)-reactivities. Immunoelectron microscopy of CLAC-positive SP showed labeling of fibrils that are more loosely dispersed compared to typical amyloid fibrils in CLAC-negative SP. In DS cerebral cortex, diffuse plaques in young patients were negative for CLAC, whereas a subset of SP became CLAC-positive in patients aged 35 to 50 years, before the appearance of Abeta40. In DS cases over 50 years of age, Abeta40-positive SP dramatically increased, whereas CLAC burden remained at a constant level. In PSAPP transgenic mice, CLAC was positive in the diffuse Abeta deposits surrounding huge-cored plaques. Thus, CLAC and Abeta40 or thioS exhibit mostly separate distribution patterns in SP, suggesting that CLAC is a relatively early component of SP in human brains that may have inhibitory effects against the maturation of SP into beta-sheet-rich amyloid deposits.