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At least 379 records · Page 21Linked to original sources
PubMed1996

The beta-amyloid domain is essential for axonal sorting of amyloid precursor protein.

We have analysed the axonal sorting signals of amyloid precursor protein (APP). Wild-type and mutant versions of human APP were expressed in hippocampal neurons using the Semliki forest virus system. We show that wild-type APP and mutations implicated in Alzheimer's disease and another brain beta-amyloidosis are sorted to the axon. By analysis of deletion mutants we found that the membrane-inserted APP ectodomain but not the cytoplasmic tail is required for axonal sorting. Systematic deletions of the APP ectodomain identified two regions required for axonal delivery: one encoded by exons 11-15 in the carbohydrate domain, the other encoded by exons 16-17 in the juxtamembraneous beta-amyloid domain. Treatment of the cells with the N-glycosylation inhibitor tunicamycin induced missorting of wild-type APP, supporting the importance of glycosylation in axonal sorting of APP. The data revealed a hierarchy of sorting signals on APP: the beta-amyloid-dependent membrane proximal signal was the major contributor to axonal sorting, while N-glycosylation had a weaker effect. Furthermore, recessive somatodendritic signals, most likely in the cytoplasmic tail, directed the protein to the dendrites when the ectodomain was deleted. Analysis of detergent solubility of APP and another axonally delivered protein, hemagglutinin, demonstrated that only hemagglutinin formed CHAPS-insoluble complexes, suggesting distinct mechanisms of axonal sorting for these two proteins. This study is the first delineation of sorting requirements of an axonally targeted protein in polarized neurons and indicates that the beta-amyloid domain plays a major role in axonal delivery of APP.

Alzheimer Disease↗
PubMed1983

Demonstration of amyloid A (AA) protein and amyloid P component (AP) in deposits of systemic amyloidosis associated with renal adenocarcinoma.

The fibril protein in three cases of systemic amyloidosis associated with renal adenocarcinoma was identified as amyloid A protein (AA) using immunohistochemical staining techniques. Amyloid P component was also present in all deposits. In one case unfixed snap frozen tissues were studied directly whilst in the other two, which were investigated retrospectively, fixed paraffin sections were stained by immunofluorescence and immunoperoxidase methods after treatment with trypsin. Enzymatic digestion was necessary to restore reactivity with anti-AP but anti-AA reacted well without any such treatment. These findings establish that renal carcinoma, the carcinoma most frequently associated with systemic amyloidosis, causes the same type of secondary or reactive systemic amyloid as chronic infections and inflammatory disorders.

Adenocarcinoma↗
PubMed2001

Neurodegenerative changes associated with beta-amyloid deposition in the brains of mice carrying mutant amyloid precursor protein and mutant presenilin-1 transgenes.

Mutations of amyloid precursor protein (APP) and presenilin-1 (PS1) lead to an increase in beta-amyloid (Abeta) production. Despite the fact that a number of transgenic mice develop cerebral Abeta plaques, few have been subjected to ultrastructural investigation and the sequence of events leading to Abeta plaque formation is unclear. We therefore investigated the doubly transgenic (mutant APP(K670N,M671L)-mutant PS1(M146L)) mouse, which develops Abeta deposits much earlier than singly transgenic littermates. Widespread Abeta plaques with or without a distinct core were found in gray matter. Abeta plaques were also present in white matter. Astrocytosis was greater around gray matter plaques than around white matter plaques. In some plaques, Abeta cores were associated with cell profiles containing prominent endoplasmic reticulum and a homogeneous cytoplasm that appeared to be neuronal. The morphology and location of other profiles indicated them to be microglia or oligodendrocytes. Some Abeta fibrils appeared to lie within these profiles, but they may have been simply surrounded by the cell profile since the profile membrane was not always visible. Dark atrophic neurons, whose morphology suggested that they were apoptotic, were present around gray matter plaques. Cerebrovascular Abeta deposition was also observed in the brains of APP/PS1 transgenic mice. Thus, the amyloid deposition and neuropathology observed in APP/PS1 mouse brain are similar to those in Alzheimer's disease and they appear to develop earlier and become more severe than in the other transgenic models currently available.

Aging↗
PubMed2006

Small heat shock protein HspB8: its distribution in Alzheimer's disease brains and its inhibition of amyloid-beta protein aggregation and cerebrovascular amyloid-beta toxicity.

Alzheimer's disease (AD) is characterized by pathological lesions, such as senile plaques (SPs) and cerebral amyloid angiopathy (CAA), both predominantly consisting of a proteolytic cleavage product of the amyloid-beta precursor protein (APP), the amyloid-beta peptide (Abeta). CAA is also the major pathological lesion in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), caused by a mutation in the gene coding for the Abeta peptide. Several members of the small heat shock protein (sHsp) family, such as alphaB-crystallin, Hsp27, Hsp20 and HspB2, are associated with the pathological lesions of AD, and the direct interaction between sHsps and Abeta has been demonstrated in vitro. HspB8, also named Hsp22 of H11, is a recently discovered member of the sHsp family, which has chaperone activity and is observed in neuronal tissue. Furthermore, HspB8 affects protein aggregation, which has been shown by its ability to prevent formation of mutant huntingtin aggregates. The aim of this study was to investigate whether HspB8 is associated with the pathological lesions of AD and HCHWA-D and whether there are effects of HspB8 on Abeta aggregation and Abeta-mediated cytotoxicity. We observed the expression of HspB8 in classic SPs in AD brains. In addition, HspB8 was found in CAA in HCHWA-D brains, but not in AD brains. Direct interaction of HspB8 with Abeta(1-42), Abeta(1-40) and Abeta(1-40) with the Dutch mutation was demonstrated by surface plasmon resonance. Furthermore, co-incubation of HspB8 with D-Abeta(1-40) resulted in the complete inhibition of D-Abeta(1-40)-mediated death of cerebrovascular cells, likely mediated by a reduction in both the beta-sheet formation of D-Abeta(1-40) and its accumulation at the cell surface. In contrast, however, with Abeta(1-42), HspB8 neither affected beta-sheet formation nor Abeta-mediated cell death. We conclude that HspB8 might play an important role in regulating Abeta aggregation and, therefore, the development of classic SPs in AD and CAA in HCHWA-D.

Aged↗
PubMed2004

Binding of cystatin C to Alzheimer's amyloid beta inhibits in vitro amyloid fibril formation.

The colocalization of cystatin C, an inhibitor of cysteine proteases, with amyloid beta (Abeta) in parenchymal and vascular amyloid deposits in brains of Alzheimer's disease (AD) patients may reflect cystatin C involvement in amyloidogenesis. We therefore sought to determine the association of cystatin C with Abeta. Immunofluorescence analysis of transfected cultured cells demonstrated colocalization of cystatin C and beta amyloid precursor protein (betaAPP) intracellularly and on the cell surface. Western blot analysis of immunoprecipitated cell lysate or medium proteins revealed binding of cystatin C to full-length betaAPP and to secreted betaAPP (sbetaAPP). Deletion mutants of betaAPP localized the cystatin C binding site within betaAPP to the Abeta region. Cystatin C association with betaAPP resulted in increased sbetaAPP but did not affect levels of secreted Abeta. Analysis of the association of cystatin C and Abeta demonstrated a specific, saturable and high affinity binding between cystatin C and both Abeta(1-42) and Abeta(1-40). Notably, cystatin C association with Abeta results in a concentration-dependent inhibition of Abeta fibril formation.

Alzheimer Disease↗
PubMed1997

Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins.

Missense mutations in two related genes, termed presenilin 1 (PS1) and presenilin 2 (PS2), cause dementia in a subset of early-onset familial Alzheimer's disease (FAD) pedigrees. In a variety of experimental in vitro and in vivo settings, FAD-linked presenilin variants influence the processing of the amyloid precursor protein (APP), leading to elevated levels of the highly fibrillogenic Abeta1-42 peptides that are preferentially deposited in the brains of Alzheimer Disease (AD) patients. In this report, we demonstrate that transgenic animals that coexpress a FAD-linked human PS1 variant (A246E) and a chimeric mouse/human APP harboring mutations linked to Swedish FAD kindreds (APP swe) develop numerous amyloid deposits much earlier than age-matched mice expressing APP swe and wild-type Hu PS1 or APP swe alone. These results provide evidence for the view that one pathogenic mechanism by which FAD-linked mutant PS1 causes AD is to accelerate the rate of beta-amyloid deposition in brain.

Aging↗
PubMed2003

Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-beta ligand in transgenic mice.

The lack of a specific biomarker makes preclinical diagnosis of Alzheimer's disease (AD) impossible, and it precludes assessment of therapies aimed at preventing or reversing the course of the disease. The development of a tool that enables direct, quantitative detection of the amyloid-beta deposits found in the disease would provide an excellent biomarker. This article demonstrates the real-time biodistribution kinetics of an imaging agent in transgenic mouse models of AD. Using multiphoton microscopy, Pittsburgh compound B (PIB) was imaged with sub-microm resolution in the brains of living transgenic mice during peripheral administration. PIB entered the brain quickly and labeled amyloid deposits within minutes. The nonspecific binding was cleared rapidly, whereas specific labeling was prolonged. WT mice showed rapid brain entry and clearance of PIB without any binding. These results demonstrate that the compound PIB has the properties required for a good amyloid-imaging agent in humans with or at risk for AD.

Alzheimer Disease↗
PubMed2005

Statins cause intracellular accumulation of amyloid precursor protein, beta-secretase-cleaved fragments, and amyloid beta-peptide via an isoprenoid-dependent mechanism.

The use of statins, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that block the synthesis of mevalonate (and downstream products such as cholesterol and nonsterol isoprenoids), as a therapy for Alzheimer disease is currently the subject of intense debate. It has been reported that statins reduce the risk of developing the disorder, and a link between cholesterol and Alzheimer disease pathophysiology has been proposed. Moreover, experimental studies focusing on the cholesterol-dependent effects of statins have demonstrated a close association between cellular cholesterol levels and amyloid production. However, evidence suggests that statins are pleiotropic, and the potential cholesterol-independent effects of statins on amyloid precursor protein (APP) metabolism and amyloid beta-peptide (A beta) genesis are unknown. In this study, we developed a novel in vitro system that enabled the discrete analysis of cholesterol-dependent and -independent (i.e. isoprenoid-dependent) statin effects on APP cleavage and A beta formation. Given the recent interest in the role that intracellular A beta may play in Alzheimer disease, we analyzed statin effects on both secreted and cell-associated A beta. As reported previously, low cellular cholesterol levels favored the alpha-secretase pathway and decreased A beta secretion presumably within the endocytic pathway. In contrast, low isoprenoid levels resulted in the accumulation of APP, amyloidogenic fragments, and A beta likely within biosynthetic compartments. Importantly, low cholesterol and low isoprenoid levels appeared to have completely independent effects on APP metabolism and A beta formation. Although the implications of these effects for Alzheimer disease pathophysiology have yet to be investigated, to our knowledge, these results provide the first evidence that isoprenylation is involved in determining levels of intracellular A beta.

Adenoviridae↗
PubMed2005

The novel beta-secretase inhibitor KMI-429 reduces amyloid beta peptide production in amyloid precursor protein transgenic and wild-type mice.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major component of the plaques, amyloid beta peptide (Abeta), is generated from amyloid precursor protein (APP) by beta- and gamma-secretase-mediated cleavage. Because beta-secretase/beta-site APP cleaving enzyme 1 (BACE1) knockout mice produce much less Abeta and grow normally, a beta-secretase inhibitor is thought to be one of the most attractive targets for the development of therapeutic interventions for AD without apparent side-effects. Here, we report the in vivo inhibitory effects of a novel beta-secretase inhibitor, KMI-429, a transition-state mimic, which effectively inhibits beta-secretase activity in cultured cells in a dose-dependent manner. We injected KMI-429 into the hippocampus of APP transgenic mice. KMI-429 significantly reduced Abeta production in vivo in the soluble fraction compared with vehicle, but the level of Abeta in the insoluble fraction was unaffected. In contrast, an intrahippocampal injection of KMI-429 in wild-type mice remarkably reduced Abeta production in both the soluble and insoluble fractions. Our results indicate that the beta-secretase inhibitor KMI-429 is a promising candidate for the treatment of AD.

Amyloid Precursor Protein Secretases↗
PubMed2004

Neutralization of transthyretin reverses the neuroprotective effects of secreted amyloid precursor protein (APP) in APPSW mice resulting in tau phosphorylation and loss of hippocampal neurons: support for the amyloid hypothesis.

Alzheimer's disease (AD) may be caused by the abnormal processing of the amyloid precursor protein (APP) and the accumulation of beta-amyloid (Abeta). The amyloid precursor protein can be proteolytically cleaved into multiple fragments, many of which have distinct biological actions. Although a high level of Abeta can be toxic, the alpha-secretase cleaved APP (sAPPalpha) is neuroprotective. However, the mechanism of sAPPalpha protection is unknown. Here, we show that sAPPalpha increases the expression levels of several neuroprotective genes and protects organotypic hippocampal cultures from Abeta-induced tau phosphorylation and neuronal death. Antibody interference and small interfering RNA knock-down demonstrate that the sAPPalpha-driven expression of transthyretin and insulin-like growth factor 2 is necessary for protection against Abeta-induced neuronal death. Mice overexpressing mutant APP possess high levels of sAPPalpha and transthyretin and do not develop the tau phosphorylation or neuronal loss characteristic of human AD. Chronic infusion of an antibody against transthyretin into the hippocampus of mice overexpressing APP with the Swedish mutation (APP(Sw)) leads to increased Abeta, tau phosphorylation, and neuronal loss and apoptosis within the CA1 neuronal field. Therefore, the elevated expression of transthyretin is mediated by sAPPalpha and protects APP(Sw) mice from developing many of the neuropathologies observed in AD.

Aging↗
PubMed2003

Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein transgenic mice.

Cerebral amyloid angiopathy (CAA) is a common cause of brain hemorrhage in the elderly. It is found in the majority of patients with Alzheimer's disease (AD). The most common form of CAA is characterized by the deposition of the amyloid-beta (Abeta) peptide in the walls of cerebral vessels, and this deposition can lead to hemorrhage and infarction. As in AD, the epsilon4 allele of apolipoprotein E (APOE) is a risk factor for CAA. To determine the effect of apoE on CAA and associated hemorrhage in vivo, we used two amyloid precursor protein (APP) transgenic mouse models that develop age-dependent Abeta deposition: PDAPP and APPsw mice. We found that both models developed an age-dependent increase in CAA and associated microhemorrhage, with the APPsw model having an earlier and more severe phenotype; however, when APPsw and PDAPP mice were bred onto an Apoe-/- background, no CAA was detected through 24 months of age, and there was little to no evidence of microhemorrhage. Biochemical analysis of isolated cerebral vessels from both PDAPP and APPsw mice with CAA revealed that, as in human CAA, the ratio of Abeta 40:42 was elevated relative to brain parenchyma. In contrast, the ratio of Abeta 40:42 from cerebral vessels isolated from old PDAPP, Apoe-/- mice was extremely low. These findings demonstrate that murine apoE markedly promotes the formation of CAA and associated vessel damage and that the effect of apoE combined with the level of Abeta40 or the ratio of Abeta 40:42 facilitates this process.

Age Factors↗
PubMed1987

Early identification of amyloid heart disease by technetium-99m-pyrophosphate scintigraphy: a study with familial amyloid polyneuropathy.

To determine whether technetium-99m-pyrophosphate (Tc-99m-PYP) scanning or two-dimensional echocardiography can detect amyloid heart disease in an earlier stage of familial amyloid polyneuropathy, 15 patients were examined. Although 10 of the 15 patients had no clinical evidence of congestive heart failure, as well as normal ventricular wall thickness and normal values for left ventricular systolic function, five (50%) of them showed mild or moderate myocardial uptake. On the other hand, none had characteristic highly refractile myocardial echoes on the two-dimensional echocardiographic images (p less than 0.01), and values for diastolic function were reduced in four of the five and normal in the remaining one. In 85 control subjects, diffuse positive pyrophosphate scans of the heart were found in four (5%) of them (three with dilated cardiomyopathy and one with sarcoidosis), and highly refractile granular sparkling echoes were observed in nine (11%) (five with hypertrophic cardiomyopathy, three with aortic stenosis, and one with hypereosinophilic syndrome). We conclude that Tc-99m-PYP scanning is a more sensitive and specific method and may have the potential ability to detect amyloid heart disease in the earlier stage of familial amyloid polyneuropathy than two-dimensional echocardiography.

Adult↗
PubMed1998

Bulbar palsy in senile onset familial amyloid polyneuropathy (30Val-->Met): transthyretin-amyloid deposits in the hypoglossal nerve root.

Japanese familial amyloid polyneuropathy (FAP type I) is characterized clinically by autonomic and sensorimotor polyneuropathy. Bulbar palsy or lower cranial amyloid neuropathy has not been reported in this disease. We report a 72-year-old man with senile onset FAP type I, who developed bulbar palsy and sensorimotor polyneuropathy without autonomic failures. He noticed dysesthesia and muscle weakness in the feet at the age of 67 years. Neurological examination showed bulbar signs and sensorimotor polyneuropathy, but not autonomic neuropathy. Electromyography showed denervation in the tongue and extremities. Sural nerve biopsy revealed a profound reduction of myelinated fibers. Neuropathological studies indicated axonal degeneration and transthyretin-amyloid deposits in the peripheral nerves and hypoglossal nerves or roots. DNA analysis demonstrated transthyretinMet30 mutation. We provide the novel possibility that bulbar palsy, due to amyloid neuropathy, can occur in FAP type I. Copyright Rapid Science Ltd

Journal Article↗
PubMed1998

Disseminated superficial porokeratosis with dermal amyloid deposits: case report and immunohistochemical study of amyloid.

The association of porokeratosis with dermal amyloid deposits is extremely rare, only three cases are reported in the literature. We describe a case of disseminated superficial porokeratosis (DSP) with clear histologic evidence of amyloid deposition in the upper dermis. The amyloid was typed with an original immunohistochemical assay based on three anticytokeratin antibodies (MNF 116, CK1, KER B). The epidermal origin of the substance (K amyloid) was demonstrated by its strong positivity for MNF 116 and KER B.

Aged↗
PubMed2006

Intracranial administration of deglycosylated C-terminal-specific anti-Abeta antibody efficiently clears amyloid plaques without activating microglia in amyloid-depositing transgenic mice.

BACKGROUND: Antibodies against the Ass peptide clear Ass deposits when injected intracranially. Deglycosylated antibodies have reduced effector functions compared to their intact counterparts, potentially avoiding immune activation. METHODS: Deglycosylated or intact C-terminal specific high affinity anti-Abeta antibody (2H6) were intracranially injected into the right frontal cortex and hippocampus of amyloid precursor protein (APP) transgenic mice. The untreated left hemisphere was used to normalize for the extent of amyloid deposition present in each mouse. Control transgenic mice were injected with an antibody against a drosophila-specific protein (amnesiac). Tissues were examined for brain amyloid deposition and microglial responses 3 days after the injection. RESULTS: The deglycosylated 2H6 antibody had lower affinity for several murine Fcgamma receptors and human complement than intact 2H6 without a change in affinity for Ass. Immunohistochemistry for Abeta and thioflavine-S staining revealed that both diffuse and compact deposits were reduced by both antibodies. In animals treated with the intact 2H6 antibody, a significant increase in Fcgamma-receptor II/III immunostaining was observed compared to animals treated with the control IgG antibody. No increase in Fcgamma-receptor II/III was found with the deglycosylated 2H6 antibody. Immunostaining for the microglial activation marker CD45 demonstrated a similar trend. CONCLUSION: These findings suggest that the deglycosylated 2H6 is capable of removing both compact and diffuse plaques without activating microglia. Thus, antibodies with reduced effector functions may clear amyloid without concomitant immune activation when tested as immunotherapy for Alzheimer's disease.

Journal Article↗
PubMed1996

Interaction of transthyretin with amyloid beta-protein: binding and inhibition of amyloid formation.

Aggregated amyloid beta-protein (A beta) is a key component of the amyloid depositions found in the brains of patients with Alzheimer's disease. In contrast, in cerebrospinal fluid (CSF), A beta is found in a soluble form. The analysis of complexes of A beta with CSF proteins in a KBr gradient revealed an association of A beta only with free proteins and not with lipoprotein particles. Transthyretin (TTR), a second major CSF protein, formed SDS-stable complexes with A beta and significantly decreased the rate of A beta fibril formation. In physiological buffers and CSF, TTR exclusively decreased the level of A beta pentamers. Endogenous TTR-A beta complexes were detected in human CSF by immunoprecipitation. Using site-directed mutagenesis and computer-assisted modelling, we identified amino acid residues on the surface of the TTR monomer that interact with A beta. Specific TTR immunoreactivity was detected in multiple cortical neurons and astrocytes in the human brain. We propose that A beta binding proteins play a key role in the modulation of A beta aggregation and normally prevent amyloid formation in biological fluids and in the brain.

Alzheimer Disease↗
PubMed1988

Inhibition of human neutrophil and Pseudomonas elastases by the amyloid P-component: a constituent of elastic fibers and amyloid deposits.

The amyloid P-component (AP), a ubiquitous component of amyloid fibrils, is also a plasma protein and a connective tissue constituent. Its proximity to elastin, in particular, suggested that AP might serve to protect elastic tissue from hydrolytic enzymes. The inhibition of pancreatic elastase by AP has been reported. In the present study, the effects of AP on human neutrophil elastase and Pseudomonas elastase were investigated, and AP was shown to interfere with the cleavage of soluble elastin. As indicated by Michaelis-Menten analysis, AP is acting as a noncompetitive inhibitor. C-reactive protein, which is structurally similar to AP, had no effect on either elastase. AP was also found to inhibit the degradation of secondary amyloid fibrils by neutrophil elastase when these structures were first partially purified and then reexposed to AP. AP's ability to inhibit elastase was compared with alpha-1 antitrypsin in the presence and absence of oxidizing agents. These substances, which are released by inflammatory cells, are known to abrogate alpha-1 antitrypsin's anti-protease capacity. This contributes to elevated levels of free proteases in the circulation and extravascular spaces during severe inflammation. AP is not susceptible to oxidation and remains a functional inhibitor under these conditions. The potential role of AP as an elastase inhibitor is discussed.

Amyloid↗
PubMed2002

Isoaspartate formation at position 23 of amyloid beta peptide enhanced fibril formation and deposited onto senile plaques and vascular amyloids in Alzheimer's disease.

Senile plaques and amyloid-bearing vessels consisting of fibrillar amyloid beta peptides (A beta) are characteristic neuropathological features of Alzheimer's disease (AD). A beta undergo spontaneous post-translational modifications, such as isomerization and racemization, at their aspartyl residues in AD brains. Here we present evidence that A beta isomerized at position 23 are deposited on plaques and vascular amyloids using an anti-isomerized A beta antibody. In vitro experiments showed that isomerization at position 23, but not position 7, enhanced aggregation. Furthermore, A beta with the Dutch mutation, but not the Flemish mutation, also showed greatly enhanced aggregation. These results suggest that mutations or modifications at positions Glu 22 and Asp 23 have a pathogenic role in the deposition of A beta. The development and progression of sporadic AD may be accelerated by spontaneous isomerization at position 23 of A beta.

Aged↗