Aβ40 is a major form of β-amyloid in nonhuman primates

Because aged nonhuman primates show β-amyloid (Aβ) deposition in senile plaques and blood vessels similar to that seen in human aging and AD, we used C-terminal specific antibodies to Aβ₄₀ and Aβ₄₂ to investigate Aβ peptide length in the brains of 11 aged rhesus monkeys and a 59-year-old chimpanzee. In contrast to AD, where the earliest and most prominent form of Aβ in senile plaques is Aβ₄₂, in the monkey, Aβ₄₀-positive plaques predominated. The ratio of Aβ₄₎: Aβ₄₂-positive plaques averaged 2.08 in the monkey, as compared to a mean ratio of 0.37 in 68 human AD subjects (p < 0.001). Aβ₄₀ was also more prominent in the chimpanzee than in humans. Possible explanations for these findings include species differences in the cleavage of Aβ from the amyloid precursor protein or in the activity of a putative carboxy peptidase forming Aβ₄₀ from Aβ₄₂ in situ.     

Incidence and characterization of age related amyloid deposits in the human anterior pituitary gland

Summary To identify amyloid deposits in the anterior pituitary gland, we have immunohistochemical, histochemical and alkaline Congo red staining. The anti-human P component reacted positively with these amyloid deposits, while antisera against prealbumin, AA type amyloid fibril protein and various anterior pituitary hormones were negative. A combination of Congo red and anti-human P component staining was most sensitive and reliable for detection of amyloid in the anterior pituitary glands of 300 randomly autopsied patients. Amyloid deposits increased in parallel with the age of the patients, however, they appeared earlier and more frequently than heretofore reported. Deposition of amyloid was seen initially in the 3rd decade and the positivity rate of amyloid deposits was 73% in the 5th decade. The histochemical characteristics of these pituitary amyloid deposits differed from those of cerebral and systemic deposits, particularly those found in the amyloid of senile systemic amyloidosis.This study was supported in part by a grant from the Fundation for Advancement of Clinical Medicine and Ministry of Health and Welfare of Japan     

siRNA干扰跨膜转运蛋白21的表达对KO小鼠胚胎成纤维细胞γ分泌酶活性的影响

目的探讨跨膜转运蛋白21（TMP21）对γ分泌酶活性的影响。 方法将淀粉样前体蛋白基因缺陷型KO小鼠胚胎成纤维细胞[MEF（KO）]分为转染组（T）和对照组（C），转染组转染载有TMP21小分子干扰RNA（siRNA）的质粒，对照组转染空质粒。每组均制备包含细胞全膜蛋白的样品（T1、C1），经CHAPSO进一步溶解后超速离心制备所得纯化全膜蛋白样品（T2、C2），用γ分泌酶组分早老蛋白1（PS-1）特异性抗体免疫沉降C2或T2后获得的γ分泌酶样品（IPT2、IPC2）。蛋白质印迹法检测各类样品中γ分泌酶重要组分TMP21、PS-1和Nicastrin（NCT）蛋白表达量；应用ELISA法检测β淀粉样肽40和β＆#61472;淀粉样肽42的生成总量。 结果蛋白质印迹法检测显示，TMP21蛋白表达量在转染组样品IPT2中为（5294±247）ng/ml，在对照组样品IPC2中为（19110±579）ng/ml，组间差异有统计学意义（P〈0.05）；各类样品中PS-1与NCT蛋白表达量无明显变化；TMP21可与PS-1共沉降。ELISA法检测显示，转染组样品IPT2与饱和浓度底物C99反应生成的β淀粉样肽40和β淀粉样肽42总量为（348±18）pg/ml，对照组样品IPC2为与饱和浓度底物C99反应生成的β淀粉样肽40和β淀粉样肽42总量为（342±18）pg/ml，组间差异有统计学意义（P〈0.01）。 结论TMP21可能为γ分泌酶的组分之一。在TMP21蛋白低表达状态下γ分泌酶活性升高，提示TMP21为γ分泌酶的负调控因子之一。     

The role of beta-catenin, TGF beta 3, NGF2, FGF2, IGFR2, and BMP4 in the pathogenesis of mesenteric sclerosis and angiopathy in midgut carcinoids

A subset of midgut carcinoids (MCs) result in mesenteric angiopathy (MA) and bowel infarction as a consequence of vascular compression caused by extensive mesenteric sclerosis (MS). The goal of this study was to determine whether the level of expression of several fibrosing-related growth factors was related to the finding of MA and/or MS in MCs. Eighteen cases of MC, 6 with both extensive MS and MA (group I), 5 with extensive MS only (group II), and 7 with ordinary MS only (group III), were analyzed for immunoexpression of beta-catenin, transforming growth factor-beta 2 (TGF beta 2), nerve growth factor 2 (NGF2), fibroblast growth factor 2 (FGF2), insulin growth factor receptor (IGFR), and bone morphogenic protein 4 (BMP4) in formalin-fixed, paraffin-embedded sections. Standard immunohistochemical technique was used following antigen retrieval. Immunostaining was scored semiquantitively as the product of the percentage and intensity (0 to 2+) of the immunostaining, giving a possible range of 0 to 200. One-way analysis of variance and Mann-Whitney nonparametric analyses were used for statistical analysis. The mean scores of immunoreactivity of each factor in groups I, II, and III were as follows: 135, 174, and 147 for beta-catenin (cytoplasmic reactivity only); 106, 112, and 92 for TGF beta 3; 1.67, 32, and 36 for NGF-2; 2.5, 48, and 55 for FGF-2; 19, 112, and 66 for IGFR2; 140, 45, and 52 for BMP4. There were significant differences in NGF-2 immunoreactivity between groups I and III (P = 0.0023) and in BMP4 immunoreactivity between groups I and II (P = 0.017) and groups I and III (P = 0.022). All MCs expressed high levels of membranous beta-catenin, moderate levels of TGF beta 3 and IGFR2, and low levels of FGF-2, with no significant differences seen among the groups. MCs with prominent MS and MA (group I) expressed significantly higher BMP4 than those in groups II and III, suggesting a potential role of BMP4 in the pathogenesis of MA. The level of NGF-2 expression was significantly lower in group I than in group III, possibly indicating abnormal angiogenesis in the formation of angiopathy.     

Generalized AA-amyloidosis in a 58-year-old Caucasian woman with an 18-month history of gastrointestinal tuberculosis

 We report on a 58-year-old Caucasian woman who went to a general practitioner about recurrent abdominal pain, night sweats and weight loss of a few weeks’ duration. Once gynaecological disease had been ruled out, the patient was admitted to hospital with severe abdominal pain and intestinal obstruction and a right-sided hemicolectomy was performed. Following the investigation of osteolytic lumbar vertebrae, 18 months after visiting the general practitioner the patient was finally found to be suffering from generalized AA-amyloidosis secondary to gastrointestinal tuberculosis. This had been misinterpreted as Crohn’s disease. Re-examination of the specimens from the right-sided hemicolectomy demonstrated that scanty deposits of AA-amyloid were present 9 months after the first presentation. AA-amyloid can thus be present in serious inflammatory disease even during the first 9 months after the initial clinical presentation. Received: 23 June 1998 / Accepted: 19 August 1998     

Type-specific evolution of amyloid plaque and angiopathy in APPsw mice

To clarify how Aβ deposits start in the brain, we examined the early to late stages of senile plaques and amyloid angiopathy in APPsw mice. All types of human senile plaques were observed in the mouse brains. The premature forms of cored plaques appeared first in the cerebral cortex of mice at 7–8 months old. Then, amyloid angiopathy emerged, followed by diffuse plaques consisting of Aβ1–42. Modifications of the N-terminus of Aβ were late phase phenomena. The premature forms of cored plaques were composed of central Aβ1–40 amyloid cores, surrounding amorphous Aβ1–42 deposits, and accumulation of Aβ1–42 in some peripheral cells. These cells were incorporated in amyloid cores, and these plaques developed to large cored plaques composed of Aβ1–40 and Aβ1–42. The size and number of cored plaques were increased with age. These findings indicate different evolution paths for cored plaques and diffuse plaques, and suggest the presence of a pathway that initiates with the intracellular accumulation of Aβ1–42 and leads to the development of classic plaques in human brain tissues.     

Uncommon Type of Meningiomas with Conspicuous Plasmo-lymphocytic Infiltration: An Immunohistochemical and Histochemical Study

Two cases of meningioma revealing conspicuous plasmo lymphocytic tissue and hyalinized fibrous tissue components are reported. Histopathological examination of the plasmo lymphocytic infiltration was performed. Both lesions showed polyclonality of plasma cells as revealed by positive reactions for 1gG and paraimmunoglobulin χ- and λ light chains, and amyloid infiltration into the fibrous stroma and blood vessel walls. The histochemical and immunohistochemical characteristics of the lesion in relation to its etiology are briefly discussed. Acta Pathol. Jpn. 32: 190∼194, 1989.     

细胞外信号调节激酶在TPPB促进PC12产生可溶性淀粉样前体蛋白中的作用

目的：观察在蛋白激酶C(PKC)激动剂TPPB促进可溶性淀粉样前体蛋白(sAPPα)释放过程中参与的信号转导通路。方法:以1 μmol/L的TPPB作用于PC12细胞3 h，同时加入信号转导通路的抑制剂，Western印迹法检测上清液内sAPPα的含量和细胞外信号调节激酶(p42/44MAPK)及磷酸化的p42/44MAPK的表达。结果:1 μmol/L的TPPB作用于PC12细胞3 h可以显著增加上清液内sAPPα的含量，细胞外信号调节激酶抑制剂U0126、c-Jun氨基末端激酶抑制剂SP600125和蛋白酪氨酸激酶抑制剂genistein可以部分消除此作用；而p38MAPK抑制剂SB203580对sAPPα的含量无显著影响。1 μmol/L的TPPB可以使磷酸化的p42/44MAPK表达增加，而对总的p42/44MAPK无显著影响。结论:细胞外信号调节激酶、c-Jun氨基末端激酶和蛋白酪氨酸激酶可能参与TPPB促进sAPPα生成的过程。     

Perivascular Drainage of Amyloid-β Peptides from the Brain and Its Failure in Cerebral Amyloid Angiopathy and Alzheimer's Disease

Alzheimer's disease is the commonest dementia. One major characteristic of its pathology is accumulation of amyloid-β (Aβ) as insoluble deposits in brain parenchyma and in blood vessel walls [cerebral amyloid angiopathy (CAA)]. The distribution of Aβ deposits in the basement membranes of cerebral capillaries and arteries corresponds to the perivascular drainage pathways by which interstitial fluid (ISF) and solutes are eliminated from the brain—effectively the lymphatic drainage of the brain. Theoretical models suggest that vessel pulsations supply the motive force for perivascular drainage of ISF and solutes. As arteries stiffen with age, the amplitude of pulsations is reduced and insoluble Aβ is deposited in ISF drainage pathways as CAA, thus, further impeding the drainage of soluble Aβ. Failure of perivascular drainage of Aβ and deposition of Aβ in the walls of arteries has two major consequences: (i) intracerebral hemorrhage associated with rupture of Aβ-laden arteries in CAA; and (ii) Alzheimer's disease in which failure of elimination of ISF, Aβ and other soluble metabolites from the brain alters homeostasis and the neuronal environment resulting in cognitive decline and dementia. Therapeutic strategies that improve elimination of Aβ and other soluble metabolites from the brain may prevent cognitive decline in Alzheimer's disease.