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1.
BACE1 and BACE2 in pathologic and normal human muscle 总被引:5,自引:0,他引:5
Vattemi G Engel WK McFerrin J Pastorino L Buxbaum JD Askanas V 《Experimental neurology》2003,179(2):150-158
BACE1 and BACE2 are recently discovered enzymes participating in processing of amyloid beta precursor protein (AbetaPP). Their discovery is contributing importantly to understanding the mechanism of amyloid-beta generation, and hence the pathogenesis of Alzheimer's disease (AD). Sporadic inclusion-body myositis (s-IBM) and hereditary inclusion-body myopathy (h-IBM) are progressive muscle diseases in which overproduction of AbetaPP and accumulation of its presumably toxic proteolytic product amyloid-beta (Abeta) in abnormal muscle fibers appear to play an important upstream role in the pathogenic cascade. In normal human muscle AbetaPP was also shown to be present and presumably playing a role (a) at neuromuscular junctions and (b) during muscle development. To investigate whether BACE1 and BACE2 play a role in normal and diseased human muscle, we have now studied them by immunocytochemistry and immunoblotting in 35 human muscle biopsies, including: 5 s-IBM; 5 chromosome-9p1-linked quadriceps-sparing h-IBM; and 25 control muscle biopsies. In addition, expression of BACE1 and BACE2 was studied in normal cultured human muscle. Our studies demonstrate that BACE1 and BACE2 (a) are expressed in normal adult muscle at the postsynaptic domain of neuromuscular junctions, and in cultured human muscle; (b) are accumulated in the form of plaque-like inclusions in both s-IBM and h-IBM vacuolated muscle fibers; and (c) are immunoreactive in necrotizing muscle fibers. Accordingly, BACE1 and BACE2 participate in normal and abnormal processes of human muscle, suggesting that their functions are broader than previously thought. 相似文献
2.
3.
Heredia L Lin R Vigo FS Kedikian G Busciglio J Lorenzo A 《Neurobiology of disease》2004,16(3):617-629
Amyloid beta protein (Abeta) deposition and neuronal degeneration are characteristic pathological features of Alzheimer's disease (AD). In vitro, Abeta fibrils (fAbeta) induce neuronal degeneration reminiscent to AD, but the mechanism of neurotoxicity is unknown. Here we show that amyloid fibrils increase the level of cell-surface full-length amyloid beta precursor protein (h-AbetaPP) and secreted AbetaPP (s-AbetaPP). Pulse-chase analysis indicated that fAbeta selectively inhibited the turnover of cell-surface AbetaPP, without altering its intracellular levels. FAbeta-induced AbetaPP accumulation was not abrogated by cycloheximide, suggesting that increased protein synthesis is not critically required. Abeta fibrils sequester s-AbetaPP from the culture medium and promote its accumulation at the cell surface, indicating that binding of Abeta fibrils mediates AbetaPP accumulation. A time course analysis of Abeta treatment showed that AbetaPP level is elevated before significant cell death can be detected, while other toxic insults do not augment AbetaPP level, suggesting that AbetaPP may be specifically involved in early stages of Abeta-induced neurodegeneration. Finally, Abeta fibrils promote clustering of h-AbetaPP in abnormal focal adhesion-like (FA-like) structures that mediate neuronal dystrophy, increasing its association with the cytoskeleton. These results indicate that the interaction of Abeta fibrils with AbetaPP is an early event in the mechanism of Abeta-induced neurodegeneration that may play a significant role in AD pathogenesis. 相似文献
4.
Gaetano Vattemi Anna Nogalska W. King Engel Carla D’Agostino Frederic Checler Valerie Askanas 《Acta neuropathologica》2009,117(5):569-574
Sporadic inclusion-body myositis (s-IBM) is the only muscle disease in which accumulation of amyloid-β (Aβ) in abnormal muscle
fibers appears to play a key pathogenic role. Increased amyloid-β precursor protein (AβPP) and Aβ accumulation have been reported
to be upstream steps in the development of the s-IBM pathologic phenotype, based on cellular and animal models. Aβ is released
from AβPP as a 40 or 42 aminoacid peptide. Aβ42 is considered more cytotoxic than Aβ40, and it has a higher propensity to
aggregate and form amyloid fibrils. Using highly specific antibodies, we evaluated in s-IBM muscle biopsies intra-muscle fiber
accumulation of Aβ40 and Aβ42-immunoreactive aggregates by light- and electron-microscopic immunocytochemistry, and quantified
their amounts by ELISA. In s-IBM, 80–90% of the vacuolated muscle fibers and 5–20% of the non-vacuolated muscle fibers contained
plaque-like Aβ42-immunoreactive inclusions, while only 69% of those fibers also contained Aβ40 deposits. By immuno-electronmicroscopy,
Aβ42 was associated with 6–10 nm amyloid-like fibrils, small electron-dense floccular clumps and larger masses of amorphous
material. Aβ40 was present only on small patches of floccular clumps and amorphous material; it was not associated with 6–10 nm
amyloid fibrils. By ELISA, in s-IBM muscle biopsies Aβ42 was present in values 8.53-44.7 pg/ml, while Aβ40 was not detectable;
normal age-matched control biopsies did not have any detectable Aβ42 or Aβ40. Thus, in s-IBM muscle fibers, Aβ42 is accumulated
more than Aβ40. We suggest that Aβ42 oligomers and their cytotoxicity may play an important role in the s-IBM pathogenesis.
Supported by grants from the National Institutes of Health (Merit Award AG16768), the Muscular Dystrophy Association and The
Myositis Association (to VA). FC is supported by the Fondation pour la Recherche Médicale. 相似文献
5.
AlphaB-crystallin immunolocalization yields new insights into inclusion body myositis 总被引:2,自引:0,他引:2
OBJECTIVE: To study the expression of the small heat shock protein, alphaB-crystallin (alphaBC), in inclusion body myositis (IBM). BACKGROUND: In humans, alphaBC is constitutively expressed in the eye lens, muscle, and heart, but not in lymphoid tissues. Induced expression of alphaBC occurs under metabolic stress, in virus-infected lymphocytes, and in degenerative brain lesions, including neurofibrillary tangles and senile plaques in AD. The previously reported pathologic similarities between AD and IBM prompted us to study alphaBC expression in IBM. METHODS: Immunolocalization of alphaBC in muscle of 11 patients with IBM, 50 patients with other muscle diseases, and 4 controls; and quantitative analysis of the frequency of fibers with 1) increased alphaBC expression in IBM and polymyositis and 2) structural abnormality (vacuolated, non-necrotic and invaded by mononuclear cells, Congo red-positive, SMI-31 positive, and ubiquitin positive) in IBM. RESULTS: We detected enhanced expression of alphaBC not only in all structurally abnormal IBM fibers, but also, and with severalfold higher frequency, in IBM fibers without significant structural abnormality (X fibers) (p values in paired t-tests < 0.001). We also found enhanced alphaBC in abnormal fibers in other diseases; X fibers, however, were extremely sparse or absent, except in two atypical cases of polymyositis refractory to immunotherapy. CONCLUSION: That the X fibers are much more frequent than the structurally abnormal fibers in IBM points to a pathogenic stressor acting upstream to the development of structural abnormalities. The identification of this stressor is now of paramount importance for deciphering the enigma of IBM. 相似文献
6.
Intra-muscle fiber accumulation of ubiquitinated protein aggregates containing several conformationally modified proteins,
including amyloid-β and phosphorylated tau, is characteristic of the pathologic phenotype of sporadic inclusion-body myositis
(s-IBM), the most common progressive degenerative myopathy of older persons. Abnormalities of protein-degradation, involving
both the 26S proteasome and autophagic-lysosomal pathways, were previously demonstrated in s-IBM muscle. NBR1 is a ubiquitin-binding
scaffold protein importantly participating in autophagic degradation of ubiquitinated proteins. Whereas abnormalities of p62,
a ubiquitin-binding protein, were previously described in s-IBM, abnormalities of NBR1 have not been reported in s-IBM. We
have now identified in s-IBM muscle biopsies that NBR1, by: (a) immunohistochemistry, was strongly accumulated within s-IBM
muscle-fiber aggregates, where it closely co-localized with p62, ubiquitin, and phosphorylated tau; (b) immunoblots, was increased
threefold (p < 0.001); and (c) immunoprecipitation, was associated with p62 and LC3. By real-time PCR, NBR1 mRNA was increased twofold
(p < 0.01). None of the various disease- and normal-control muscle biopsies had any NBR1 abnormality. In cultured human muscle
fibers, NBR1 also physically associated with both p62 and LC3, and experimental inhibition of either the 26S proteasome or
the lysosomal activity resulted in NBR1 increase. Our demonstration of NBR1 abnormalities in s-IBM provides further evidence
that altered protein degradation pathways may be critically involved in the s-IBM pathogenesis. Accordingly, attempts to unblock
defective protein degradation might be a therapeutic strategy for s-IBM patients. 相似文献
7.
Anna Nogalska Carla D’Agostino W. King Engel William L. Klein Valerie Askanas 《Acta neuropathologica》2010,120(5):661-666
Accumulation of amyloid-β (Aβ) within muscle fibers has been considered an upstream step in the development of the s-IBM pathologic
phenotype. Aβ42, which is considered more cytotoxic than Aβ40 and has a higher propensity to oligomerize, is preferentially
increased in s-IBM muscle fibers. In Alzheimer disease (AD), low-molecular weight Aβ oligomers and toxic oligomers, also referred
to as “Aβ-Derived Diffusible Ligands” (ADDLs), are considered strongly cytotoxic and proposed to play an important pathogenic
role. ADDLs have been shown to be increased in AD brain. We now report for the first time that in s-IBM muscle biopsies Aβ-dimer,
-trimer, and -tetramer are identifiable by immunoblots. While all the s-IBM samples we studied had Aβ-oligomers, their molecular
weights and intensity varied between the patient samples. None of the control muscle biopsies had Aβ oligomers. Dot-immunoblots
using highly specific anti-ADDL monoclonal antibodies also showed highly increased ADDLs in all s-IBM biopsies studied, while
controls were negative. By immunofluorescence, in some of the abnormal s-IBM muscle fibers ADDLs were accumulated in the form
of plaque-like inclusions, and were often increased diffusely in very small fibers. Normal and disease-controls were negative.
By gold-immuno-electron microscopy, ADDL-immunoreactivities were in close proximity to 6–10 nm amyloid-like fibrils, and also
were immunodecorating amorphous and floccular material. In cultured human muscle fibers, we found that inhibition of autophagy
led to the accumulation of Aβ oligomers. This novel demonstration of Aβ42 oligomers in s-IBM muscle biopsy provides additional
evidence that intra-muscle fiber accumulation of Aβ42 oligomers in s-IBM may contribute importantly to s-IBM pathogenic cascade. 相似文献
8.
Qiu WQ Sun X Selkoe DJ Mwamburi DM Huang T Bhadela R Bergethon P Scott TM Summergrad P Wang L Rosenberg I Folstein M 《International journal of geriatric psychiatry》2007,22(6):536-542
BACKGROUND: Depression often precedes the onset of Alzheimer's disease (AD) before the appearance of cognitive symptoms. Plasma Amyloid-beta peptide 42 (Abeta42) declines before and soon after the onset of AD, yet the relationship between plasma Abeta42 and depression is unclear. METHODS: We used 515 homebound elders aged 60 and older in a population-based, cross-sectional study to investigate associations between plasma Abeta levels and depression with and without cardiovascular co-morbidities. Depression was evaluated by using the Center for Epidemiological Studies Depression (CES-D) scale. Plasma Abeta40 and Abeta42 were measured. RESULTS: The elderly with depression had lower plasma Abeta42 (median: 15.3 vs. 18.9, p = 0.008) than those without depression. The CES-D score was inversely associated with plasma Abeta42 (p = 0.001) in subjects with no cardiovascular disease (CVD); however, in the presence of CVD, this association did not exist. Low plasma Abeta42 (OR = 0.41, p = 0.007) and the presence of CVD (OR = 1.84, p = 0.005) were independently associated with depression after adjusting for the confounders of age, stroke and apolipoprotein E4. CONCLUSIONS: Depressive symptoms are associated with low plasma Abeta42 independently of CVD. Prospective studies are needed to determine whether depression associated with low plasma Abeta42 is a separate depression subtype that could predict the onset of AD. 相似文献
9.
Increased amyloid-β precursor protein (AβPP) and amyloid-β (Aβ) accumulation appear to be upstream steps in the pathogenesis
of sporadic inclusion-body myositis (s-IBM). BACE1, participating in Aβ production is also increased in s-IBM muscle fibers.
Nogo-B and Nogo-A belong to a family of integral membrane reticulons, and Nogo-B binding to BACE1 blocks BACE1 access to AβPP,
decreasing Aβ production. We studied Nogo-B and Nogo-A in s-IBM muscle and in our IBM muscle culture models, based on AβPP-overexpression
or ER-stress-induction in cultured human muscle fibers (CHMFs). We report that: (1) in biopsied s-IBM fibers, Nogo-B is increased,
accumulates in aggregates, is immuno-co-localized with BACE1, and binds to BACE1; Nogo-A is undetectable. (2) In CHMFs, (a)
AβPP overexpression increases Nogo-B, Nogo-A, and BACE1, (b) ER stress increases BACE1 but decreases Nogo-B and Nogo-A, (c)
Nogo-B and Nogo-A associate with BACE1. Accordingly, two novel mechanisms, AβPP overexpression and ER stress, are involved
in Nogo-B and Nogo-A expression in human muscle. We propose that in s-IBM muscle the Nogo-B increase may represent an attempt
by muscle fiber to decrease Aβ production. However, the increase of Nogo-B seems insufficient because Aβ continues to accumulate
and the disease progresses. We propose that manipulations, which increase Nogo-B in s-IBM muscle might offer a new therapeutic
opportunity.
Supported by grants (to VA) from the National Institutes of Health (AG 16768 Merit Award), the Muscular Dystrophy Association,
and The Myositis Association (to VA), and the Helen Lewis Research Fund. 相似文献
10.
Askanas V Engel WK Alvarez RB McFerrin J Broccolini A 《Journal of neuropathology and experimental neurology》2000,59(7):592-598
Alpha-synuclein (alpha-syn) is an important component of neuronal and glial inclusions in brains of patients with several neurodegenerative disorders. Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle disease of older patients. Its muscle phenotype shows several similarities with Alzheimer disease brain. A distinct feature of s-IBM pathology is specific vacuolar degeneration of muscle fibers characterized by intracellular amyloid inclusions formed by both amyloid-beta (Abeta) and paired-helical filaments composed of phosphorylated tau. We immunostained alpha-syn in muscle biopsies of s-IBM, disease-control, and normal patients. Approximately 60% of Abeta-positive vacuolated muscle fibers (VMF) contained well-defined inclusions immunoreactive with antibodies against alpha-syn. In those fibers. alpha-syn co-localized with Abeta, both by light microscopy, and ultrastructurally. Paired-helical filaments did not contain alpha-syn immunoreactivity. In all muscle biopsies, alpha-syn was strongly immunoreactive at the postsynaptic region of the neuromuscular junctions. alpha-syn immunoreactivity also occurred diffusely in regenerating and necrotic muscle fibers. In cultured human muscle fibers, alpha-syn and its mRNA were expressed by immunocytochemistry, immunoblots, and Northern blots. Our study provides the first demonstration that alpha-syn participates in normal and pathologic processes of human muscle. Therefore. its function is not exclusive to the brain and neurodegenerative diseases. 相似文献
11.
Anna Nogalska Chiara Terracciano Carla D’Agostino W. King Engel Valerie Askanas 《Acta neuropathologica》2009,118(3):407-413
p62, also known as sequestosome1, is a shuttle protein transporting polyubiquitinated proteins for both the proteasomal and
lysosomal degradation. p62 is an integral component of inclusions in brains of various neurodegenerative disorders, including
Alzheimer disease (AD) neurofibrillary tangles (NFTs) and Lewy bodies in Parkinson disease. In AD brain, the p62 localized
in NFTs is associated with phosphorylated tau (p-tau). Sporadic inclusion-body myositis (s-IBM) is the most common progressive
muscle disease associated with aging, and its muscle tissue has several phenotypic similarities to AD brain. Abnormal accumulation
of intracellular multiprotein inclusions, containing p-tau in the form of paired helical filaments, amyloid-β, and several
other “Alzheimer-characteristic proteins”, is a characteristic feature of the s-IBM muscle fiber phenotype. Diminished proteasomal
and lysosomal protein degradation appear to play an important role in the formation of intra-muscle-fiber inclusions. We now
report that: (1) in s-IBM muscle fibers, p62 protein is increased on both the protein and the mRNA levels, and it is strongly
accumulated within, and as a dense peripheral shell surrounding, p-tau containing inclusions, by both the light- and electron-microscopy.
Accordingly, our studies provide a new, reliable, and simple molecular marker of p-tau inclusions in s-IBM muscle fibers.
The prominent p62 immunohistochemical positivity and pattern diagnostically distinguish s-IBM from polymyositis and dermatomyositis.
(2) In normal cultured human muscle fibers, experimental inhibition of either proteasomal or lysosomal protein degradation
caused substantial increase of p62, suggesting that similar in vivo mechanisms might contribute to the p62 increase in s-IBM
muscle fibers. 相似文献
12.
Sporadic-inclusion body myositis (s-IBM) is the most common progressive muscle disease of older persons. It leads to pronounced muscle fiber atrophy and weakness, and there is no successful treatment. We have previously shown that myostatin precursor protein (MstnPP) and myostatin (Mstn) dimer are increased in biopsied s-IBM muscle fibers, and proposed that MstnPP/Mstn increase may contribute to muscle fiber atrophy and weakness in s-IBM patients. Mstn is known to be a negative regulator of muscle fiber mass. It is synthesized as MstnPP, which undergoes posttranslational processing in the muscle fiber to produce mature, active Mstn. To explore possible mechanisms involved in Mstn abnormalities in s-IBM, in the present study we utilized primary cultures of normal human muscle fibers and experimentally modified the intracellular micro-environment to induce endoplasmic-reticulum (ER)-stress, thereby mimicking an important aspect of the s-IBM muscle fiber milieu. ER stress was induced by treating well-differentiated cultured muscle fibers with either tunicamycin or thapsigargin, both well-established ER stress inducers. Our results indicate for the first time that the ER stress significantly increased MstnPP mRNA and protein. The results also suggest that in our system ER stress activates NF-kappaB, and we suggest that MstnPP increase occurred through the ER-stress-activated NF-kappaB. We therefore propose a novel mechanism leading to the Mstn increase in s-IBM. Accordingly, interfering with pathways inducing ER stress, NF-kappaB activation or its action on the MstnPP gene promoter might prevent Mstn increase and provide a new therapeutic approach for s-IBM and, possibly, for muscle atrophy in other neuromuscular diseases. 相似文献
13.
Mazur-Kolecka B Frackowiak J Krzeslowska J Ramakrishna N Haske T Emmerling MR Zhang W Kim KS Wisniewski HM 《Journal of neuropathology and experimental neurology》1999,58(3):288-295
Canine smooth muscle cells (SMCs), cultured from amyloid-affected brain blood vessels accumulate Alzheimer amyloid-beta peptide (Abeta) intracellularly, either spontaneously or after treatment with apolipoprotein E (apoE). ApoE is codeposited with Abeta, which suggests that apoE participates in Abeta accumulation. We tested the hypothesis that apoE-induced accumulation of Abeta in SMCs is caused by an increased production of amyloid-beta precursor protein (AbetaPP) and/or its altered metabolism. We found that 24 hours of treatment with apoE3 or apoE4 induced intracellular accumulation of Abeta-immunoreactive deposits in SMCs but did not influence AbetaPP production and processing. The treatment with apoE3 or E4 for 3 days resulted in the following: increased Abeta-accumulation; reduced levels of secreted Abeta; increased production and cellular retention of mature AbetaPP770; and reduced culture growth, cell proliferation, and viability. ApoE4, but not apoE3, increased cellular levels of mRNA AbetaPP 770 (the main form produced in SMCs) about ninefold. ApoE3 stimulated production and cellular retention of endogenous apoE. We hypothesize that Abeta accumulation is triggered by apoE, which may bind and immobilize soluble Abeta produced in SMCs. The newly formed Abeta deposits may further accelerate Abeta accumulation by altering metabolism of AbetaPP. 相似文献
14.
Activated glia, as a result of chronic inflammation, are associated with amyloid-beta peptide (Abeta) deposits in the brain of Alzheimer's disease (AD) patients. In vitro, glia are activated by Abeta inducing secretion of pro-inflammatory molecules. Recent studies have focused on soluble oligomers (or protofibrils) of Abeta as the toxic species in AD. In the present study, using rat astrocyte cultures, oligomeric Abeta induced initial high levels of IL-1beta decreasing over time and, in contrast, fibrillar Abeta increased IL-1beta levels over time. In addition, oligomeric Abeta, but not fibrillar Abeta, induced high levels of iNOS, NO, and TNF-alpha. Our results suggest that oligomers induced a profound, early inflammatory response, whereas fibrillar Abeta showed less increase of pro-inflammatory molecules, consistent with a more chronic form of inflammation. 相似文献
15.
The muscle-fiber phenotype of sporadic inclusion-body myositis (s-IBM), the most common muscle disease associated with aging, shares several pathological abnormalities with Alzheimer disease (AD) brain, including accumulation of amyloid-β 42 (Aβ42) and its cytotoxic oligomers. The exact mechanisms leading to Aβ42 production within s-IBM muscle fibers are not known. Aβ42 and Aβ40 are generated after the amyloid-precursor protein (AβPP) is cleaved by β-secretase and the γ-secretase complex. Aβ42 is considered more cytotoxic than Aβ40, and it has a higher propensity to oligomerize, form amyloid fibrils, and aggregate. Recently, we have demonstrated in cultured human muscle fibers that experimental inhibition of lysosomal enzyme activities leads to Aβ42 oligomerization. In s-IBM muscle, we here demonstrate prominent abnormalities of the γ-secretase complex, as evidenced by: a) increase of γ-secretase components, namely active presenilin 1, presenilin enhancer 2, nicastrin, and presence of its mature, glycosylated form; b) increase of mRNAs of these γ-secretase components; c) increase of γ-secretase activity; d) presence of an active form of a newly-discovered γ-secretase activating protein (GSAP); and e) increase of GSAP mRNA. Furthermore, we demonstrate that experimental inhibition of lysosomal autophagic enzymes in cultured human muscle fibers a) activates γ-secretase, and b) leads to posttranslational modifications of AβPP and increase of Aβ42. Since autophagy is impaired in biopsied s-IBM muscle, the same mechanism might be responsible for its having increased γ-secretase activity and Aβ42 production. Accordingly, improving lysosomal function might be a therapeutic strategy for s-IBM patients. 相似文献
16.
Secretion and accumulation of Abeta by brain vascular smooth muscle cells from AbetaPP-Swedish transgenic mice 总被引:4,自引:0,他引:4
Frackowiak J Miller DL Potempska A Sukontasup T Mazur-Kolecka B 《Journal of neuropathology and experimental neurology》2003,62(6):685-696
Alzheimer amyloid-beta is deposited in the neuropil and in brain blood vessels in transgenic Tg2576 mice that overexpress human amyloid-beta precursor protein (AbetaPP) containing the Swedish mutation (AbetaPP-Swe). Because the AbetaPP transgene in Tg2576 mice is placed behind the PrP promoter, all amyloid-beta, including vascular amyloid, is considered to be of neuronal origin. We studied the expression of the transgenic AbetaPP in smooth muscle cells cultured from brain blood vessels from Tg2576 mice. We found that brain vascular smooth muscle cells overexpressed human AbetaPP-Swe approximately 4 times the physiological levels of mouse AbetaPP. The cultured cells secreted abundant Abeta1-40 and Abeta1-42 and formed intracellular Abeta-immunoreactive granules. The percentage of cells containing intracellular Abeta and the amount of intracellular Abeta were significantly higher in cultures obtained from 14-month-old than from 4-month-old mice, as tested on first or second passages. During cell senescence in culture, intracellular accumulation of Abeta and C-terminal fragments of AbetaPP increased in cells derived from both 4- and 14-month-old mice. Vascular muscle cells from Tg2576 mice appear to be a valuable model of the intracellular accumulation of Abeta. We suggest that vascular muscle cells may be involved in the production of cerebrovascular amyloid in Tg2576 mice. 相似文献
17.
Jaworska-Wilczynska M Wilczynski GM Engel WK Strickland DK Weisgraber KH Askanas V 《Neurology》2002,58(3):438-445
BACKGROUND: An important aspect of inclusion-body myositis (IBM) vacuolated muscle fibers (VMF) is abnormal accumulation of amyloid-beta precursor protein (AbetaPP) epitopes and its product, amyloid-beta (Abeta), and of phosphorylated tau (p-tau) in the form of paired helical filaments. Lipoprotein receptors and cholesterol are known to play an important role in AbetaPP processing, Abeta production, and tau phosphorylation. METHODS: In 10 IBM and 22 control muscle biopsies the authors immunolocalized low-density lipoprotein receptor (LDLR), very low-density lipoprotein receptor (VLDLR), and low-density lipoprotein receptor-related protein (LRP), and colocalized them with Abeta, p-tau, APOE, and free cholesterol. RESULTS: In each biopsy, virtually all IBM VMF had strong LDLR-immunoreactive inclusions, which colocalized with Abeta, APOE, p-tau, and free cholesterol. VLDLR was increased mainly diffusely, but in approximately 50% of the VMF it was also accumulated in the form of inclusions colocalizing with Abeta, APOE, and free cholesterol, but not with p-tau. LRP inclusions were present in a few VMF. In all myopathies, a subset of regenerating and necrotizing muscle fibers had prominent diffuse accumulation of both LDLR and free cholesterol. At normal neuromuscular junctions (NMJ) postsynaptically, LDLR and VLDLR, but not LRP, were immunoreactive. CONCLUSIONS: 1) Abnormal accumulation of LDLR, VLDLR, LRP, and cholesterol within IBM vacuolated muscle fibers suggests novel roles for them in the IBM pathogenesis. 2) Expression of LDLR and VLDLR at normal NMJ suggests physiologic roles for them in transsynaptic signaling pathways, increased internalization of lipoproteins there, or both. 3) Increased LDLR and free cholesterol in some regenerating and necrotizing muscle fibers suggest a role for them in human muscle fiber growth and repair and necrotic death. 相似文献
18.
Kim YH Choi MY Kim YS Han JM Lee JH Park CH Kang SS Choi WS Cho GJ 《Neurobiology of disease》2007,28(3):293-303
We investigated the relationship between phosphorylation of alphaB-crystallin (alphaBC) and retinal apoptosis in type 2 diabetes. The retinas of male Otsuka Long-Evans Tokushima fatty (OLETF) rats at 24 and 35 weeks were used as an animal model for type 2 diabetes and sex- and age-matched Long-Evans Tokushima Otsuka (LETO) rats were used as controls. In the retinas of 35-week OLETF rats, the interaction between alphaBC and protein kinase C delta (PKC delta) among the PKC isozymes, alphaBC phosphorylation at Ser45 (S45p-alphaBC), TUNEL-positive apoptotic ganglion cells, several apoptotic signs, and co-localization of S45p-alphaBC and TUNEL significantly increased as compared with other groups while the alphaBC-Bax interaction greatly decreased. These changes were abolished by rottlerin treatment, a highly specific PKC delta inhibitor. These results suggest that PKC delta is involved in regulation of anti-apoptotic function of alphaBC in the retina of type 2 diabetes. 相似文献
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20.
We examined the effects of co-incubating nine different Abeta peptide fragments with full-length Abeta1-40 (Abeta40) on protein aggregation. Six fragments enhanced aggregation of Abeta40 (Abeta1-28, 12-28, 17-28, 10-20, 25-35 and 17-40), while three others did not (Abeta1-11, 1-16, and 20-29). All of the peptides that enhanced aggregation contained either residues 17-20 or 30-35, indicating the importance of these regions for promoting aggregation of full-length Abeta. Abeta25-35 in particular increased both the rate and extent of aggregation of Abeta40 considerably as indicated by fluorescence staining. Atomic force microscope imaging (AFM) indicates the increase in fluorescence staining with Abeta25-35 is primarily due to increased formation of oligomers and protofibrils rather than formation of large amyloid fibrils. AFM images of Abeta25-35 when incubated alone also indicate formation of aggregates and long thin filaments. The increase in formation of the small toxic oligomeric morphology of Abeta40, along with formation of Abeta25-35 oligomers and thin filaments, represent two different potential pathways for Abeta25-35 toxicity. The critical roles of residues 17-20 and 30-35 of Abeta provide further insight into mechanism that underlie the formation of toxic aggregates in Alzheimer Disease (AD) and suggest targets for the design of beta-sheet breakers to modulate the aggregation and inhibit toxicity of full-length Abeta. 相似文献