Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “AMYLOID”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 307 records · Page 17Linked to original sources
PubMed1999

Non-Abeta component of Alzheimer's disease amyloid (NAC) revisited. NAC and alpha-synuclein are not associated with Abeta amyloid.

alpha-Synuclein (alphaSN), also termed the precursor of the non-Abeta component of Alzheimer's disease (AD) amyloid (NACP), is a major component of Lewy bodies and Lewy neurites pathognomonic of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). A fragment of alphaSN termed the non-Abeta component of AD amyloid (NAC) had previously been identified as a constituent of AD amyloid plaques. To clarify the relationship of NAC and alphaSN with Abeta plaques, antibodies were raised to three domains of alphaSN. All antibodies produced punctate labeling of human cortex and strong labeling of Lewy bodies. Using antibodies to alphaSN(75-91) to label cortical and hippocampal sections of pathologically proven AD cases, we found no evidence for NAC in Abeta amyloid plaques. Double labeling of tissue sections in mixed DLB/AD cases revealed alphaSN in dystrophic neuritic processes, some of which were in close association with Abeta plaques restricted to the CA1 hippocampal region. In brain homogenates alphaSN was predominantly recovered in the cytosolic fraction as a 16-kd protein on Western analysis; however, significant amounts of aggregated and alphaSN fragments were also found in urea extracts of SDS-insoluble material from DLB and PD cases. NAC antibodies identified an endogenous fragment of 6 kd in the cytosolic and urea-soluble brain fractions. This fragment may be produced as a consequence of alphaSN aggregation or alternatively may accelerate aggregation of the full-length alphaSN.

Alzheimer Disease↗
PubMed1996

Evidence that the 42- and 40-amino acid forms of amyloid beta protein are generated from the beta-amyloid precursor protein by different protease activities.

Cerebral deposition of the amyloid beta protein (A beta) is an early and invariant feature of Alzheimer disease (AD). Whereas the 40-amino acid form of A beta (A beta 40) accounts for approximately 90% of all A beta normally released from cells, it appears to contribute only to later phases of the pathology. In contrast, the longer more amyloidogenic 42-residue form (A beta 42), accounting for only approximately 10% of secreted A beta, is deposited in the earliest phase of AD and remains the major constituent of most amyloid plaques throughout the disease. Moreover, its levels have been shown to be increased in all known forms of early-onset familial AD. Thus, inhibition of A beta 42 production is a prime therapeutic goal. The same protease, gamma-secretase, is assumed to generate the C termini of both A beta 40 and A beta 42. Herein, we analyze the effect of the compound MDL 28170, previously suggested to inhibit gamma-secretase, on beta-amyloid precursor protein processing. By immunoprecipitating conditioned medium of different cell lines with various A beta 40- and A beta 42-specific antibodies, we demonstrate a much stronger inhibition of the gamma-secretase cleavage at residue 40 than of that at residue 42. These data suggest that different proteases generate the A beta 40 and A beta 42 C termini. Further, they raise the possibility of identifying compounds that do not interfere with general beta-amyloid precursor protein metabolism, including A beta 40 production, but specifically block the generation of the pathogenic A beta 42 peptide.

Amino Acid Sequence↗
PubMed2003

[Estrogen: regulation of amyloid-beta protein metabolism and attenuation of amyloid-beta protein neurotoxicity].

Alzheimer's disease(AD) is characterized by two pathological lesions: intracellular neurofibrillary tangles and extracellular amyloid deposits. Recently researchers accept the amyloid hypothesis which states that accumulation of amyloid-beta protein (A beta) in the brain is the primary causal factor driving AD pathogenesis. Since estrogen has been demonstrated to be able to modulate the metabolism of amyloid-beta precursor protein, reduce the generation of A beta, ameliorate the injury caused by inflammation and oxidative stress, and exhibit an antiapoptotic effect, it is considered that estrogen is of benefit to the prevention of AD.

Alzheimer Disease↗
PubMed1989

Radionuclide angiographic assessment of left ventricular diastolic filling in amyloid heart disease: a study of patients with familial amyloid polyneuropathy.

To assess left ventricular diastolic filling in amyloid heart disease, 17 patients with familial amyloid polyneuropathy and 20 normal subjects were examined by radionuclide angiography. None of the patients showed clinical evidence of restrictive cardiomyopathy. All but two patients had normal left ventricular ejection fraction. Peak filling rate was significantly lower and time to peak filling rate was significantly greater in patients than in normal subjects (2.60 +/- 0.52 versus 3.10 +/- 0.44 EDV/s, p less than 0.001, and 215 +/- 53 versus 147 +/- 18 ms, p less than 0.001, respectively). The mean left ventricular filling volume during rapid diastolic filling and atrial systole in patients was 54.5 +/- 19.5% and 44.2 +/- 21.6% of the stroke volume, respectively, compared with 83.8 +/- 6.6% (p less than 0.001) and 20.0 +/- 6.0% (p less than 0.001), respectively, in normal subjects. Although 10 of the 14 patients without clinical evidence of overt heart disease had normal ventricular wall thickness as well as normal ejection fraction, 8 of the 10 showed abnormal diastolic filling. In patients with familial amyloid polyneuropathy, indexes of diastolic filling were significantly related to ventricular wall thickness alone. The incidence and magnitude of abnormalities in time to peak filling rate and contribution of rapid filling as well as atrial systole to ventricular filling increased with age and duration of illness. Thus, abnormal diastolic filling can be seen even in the early stage of familial amyloid polyneuropathy and may be related to myocardial amyloid deposition as well as to fibrosis. Careful consideration should be given to age and duration of illness when diastolic filling is assessed in this disorder.

Adult↗
PubMed1996

Ageing and amyloid fibrillogenesis: lessons from apolipoprotein AI, transthyretin and islet amyloid polypeptide.

The age-associated (or senile) amyloidoses encompass a heterogeneous group of systemic or localized forms of amyloidosis. In this paper we present an overview of three age-associated amyloid forms derived from transthyretin, apolipoprotein AI and islet amyloid polypeptide. Mutations in the respective genes give rise to transthyretin and apolipoprotein AI forms of familial amyloidosis while senile forms of amyloid are associated with the wild-type proteins. Different mechanisms are probably of importance in the fibrillogenesis associated with these three amyloid types. It is also possible that different amyloidogenic pathways exist for a single amyloidogenic protein. Thus, limited proteolysis may be necessary in the fibrillogenesis in senile transthyretin amyloidosis but not in most familial transthyretin amyloidoses. Other factors in the pathogenesis of amyloidosis such as local concentration, nidus formation and glycation are also discussed.

Aging↗
PubMed2001

Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy.

Several mutations in the amyloid precursor protein (APP) gene have been found to associate with pathologic deposition of the beta-amyloid peptide (Abeta) in neuritic plaques or in the walls of cerebral vessels. We report a mutation at a novel site in APP in a three-generation Iowa family with autosomal dominant dementia beginning in the sixth or seventh decade of life. The proband and an affected brother had progressive aphasic dementia, leukoencephalopathy, and occipital calcifications. Neuropathological examination of the proband revealed severe cerebral amyloid angiopathy, widespread neurofibrillary tangles, and unusually extensive distribution of Abeta40 in plaques. The affected brothers shared a missense mutation in APP, resulting in substitution of asparagine for aspartic acid at position 694. This site corresponds to residue 23 of Abeta, thus differing from familial Alzheimer's disease mutations, which occur outside the Abeta sequence. Restriction enzyme analysis of DNA from 94 unrelated patients with sporadic cerebral amyloid angiopathy-related hemorrhage found no other instances of this mutation. These results suggest a novel site within Abeta that may promote its deposition and toxicity.

Age of Onset↗
PubMed1996

The fibril forming region of the beta-amyloid precursor differs from that of the amyloid A precursor in its interaction with lipids.

Since the amyloid A (AA) precursoir, serum amyloid A (apoSAA), has been shown to bind cholesterol (C) in the AA fibril forming region, we investigated the interaction of the beta-amyloid precursor protein (AbetaPP) and beta-amyloid (Abeta) peptide with C and phosphatidyl choline (PC) by measuring changes in binding to microtiter wells at physiological pH and ionic strength. While either C or PC inhibited AbetaPP binding to the same extent that C inhibited apoSAA binding, neither C nor PC had any effect on binding of the Abeta peptide, although antibodies to Abeta1-40 did block binding. The binding of (125)I-Abeta1-40 and (125)I-AbetaPP was inhibited by apoE3 and apoE4, but not by either apoSAA or bovine serum albumin. Bound (125)I-AbetaPP was partially released into medium containing C, PC, apoE3, apoE4, or antibodies to AbetaPP. Our results indicate that AbetaPP but not Abeta peptide can be retained in solution in the presence of C and PC and suggest that this failure to interact with lipids may account for the greater insolubility of Abeta fibrils than AA fibrils.

Amyloid beta-Protein Precursor↗
PubMed1996

Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation.

Patients with trisomy 21 [Down syndrome (DS)] progressively develop amyloid beta-protein (A beta) deposits and then other features of Alzheimer's disease (AD), apparently due to increased gene dosage and thus expression of the beta-amyloid precursor protein. Because the neuropathological phenotype in older DS subjects closely resembles that of AD, the examination of DS brains of increasing age provides a unique model of the progression of AD. Here, we characterized the deposition of several A beta peptides and apolipoprotein E in formalin-fixed brain sections from 29 DS subjects between 3 and 73 years old. Amyloid plaque number and the percentage of cortical area they occupied were quantified by computerized image analysis. A beta ending at amino acid 42 (A beta 42) was the earliest form of A beta deposited in DS cortex. It was observed in 7 of 16 young (3-30 years) subjects, with the earliest deposition occurring at age 12. A beta ending at residue 40 (A beta 40) was not detected until approximately age 30, a time when degenerating neurites around A beta immunoreactive (IR) plaques were first observed, and the frequency of A beta 40 IR plaques then rose with age. Even in old (51-73 years) DS subjects, A beta 42 IR plaques were always more abundant than A beta 40 IR plaques. A beta peptides starting at aspartate 1 or pyroglutamate 3 were detected in small subsets of compacted, neuritic plaques beginning around age 30 and rose with age, the latter species always exceeding the former. Thus, the N-termini of the A beta 42 peptides abundantly deposited in very young DS subjects remain unknown. Apo E was detectable in a small subset of A beta 42 IR plaques beginning at age 12 and rose steadily with age; it clearly followed the deposition of A beta. Our analysis of very young DS brains suggests that amyloid plaque formation begins with A beta 42-ending peptides, and the number and percentage of cortical area of A beta 42 plaques increase very little with advancing age, while other heterogeneous A beta species and Apo E progressively accrue onto plaques containing A beta 42.

Adolescent↗
PubMed1992

Spinal cord vascular and leptomeningeal amyloid beta-protein deposition in a case with cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid fibrils on leptomeningeal and cortical blood vessels, and the incidence of this disorder increases with age. However, this form of vascular amyloid deposition rarely involves tissues outside of the brain. A 71-year-old woman first developed some deterioration in memory, and soon afterwards suffered from recurrent episodes of subcortical hemorrhage. Histopathological examination of this case revealed typical pathology of Alzheimer's disease with an extensive appearance of beta-protein type CAA, and additionally, the spinal leptomeningeal vessels and the pia-arachnoid membranes were also affected by amyloid beta-protein deposits. The spinal cord involvement associated with CAA and Alzheimer's disease is unusual, and the present case provides additional important information on the pathogenesis of disorders with beta-protein deposition including Alzheimer's disease.

Aged↗
PubMed1992

Amyloid-like properties of a synthetic peptide corresponding to the carboxy terminus of beta-amyloid protein precursor.

A synthetic peptide whose sequence corresponds to the 20 carboxy-terminal amino acids of beta-amyloid protein precursor (APP) was found to form fibrils in vitro. These fibrils showed birefringence in polarized light when stained with Congo red, fluoresced when bound with thioflavin S, were resistant to proteases, and had a cross-beta conformation. By contrast, peptides with other sequences from the intracellular domain of APP and a peptide corresponding to this entire domain did not exhibit the full range of beta-amyloid properties. These results suggest that a fragment from the C-terminus of the beta-amyloid protein precursor could bind to intraneuronal paired helical filaments and account for some of its amyloid-like properties.

Amino Acid Sequence↗
PubMed1995

Neutral endopeptidase can hydrolyze beta-amyloid(1-40) but shows no effect on beta-amyloid precursor protein metabolism.

High performance liquid chromatographic analyses of incubations of beta-amyloid(1-40) with neutral endopeptidase revealed at least nine product peaks, indicating that neutral endopeptidase can cleave beta-amyloid at multiple sites. Mass spectroscopic analysis of hydrolyzed beta-amyloid identified at least five cleavage sites, between residues Glu3-Phe4, Gly9-Trp10, Phe19-Phe20, Ala30-Ile31, and Gly33-Leu34. In contrast, amyloid precursor protein metabolism in Neuro2A cells was unaffected by the expression of recombinant neutral endopeptidase in the same cells or by the addition of a secreted form of neutral endopeptidase to spent Neuro2A cell media.

Amino Acid Sequence↗
PubMed1992

Characterization of amyloid fibril protein from a case of cerebral amyloid angiopathy showing immunohistochemical reactivity for both beta protein and cystatin C.

We isolated and carried out a chemical analysis of the amyloid fibril protein from the leptomeningeal vessels of a case with non-hereditary cerebral amyloid angiopathy (CAA) showing dual immunohistochemical reactivity with antibodies to both beta-protein and cystatin C. A crude amyloid fibril fraction reacted only with anti-beta-protein antibody, and cystatin C immunoreactivity was observed in the first PBS supernatant. Complete amino acid sequence of this cystatin C-immunoreactive protein showed a homologous structure to that of normal cystatin C. It is concluded that cystatin C is not an intrinsic component of the amyloid fibril in this type of CAA.

Aged↗
PubMed1988

The potential significance of sulphated glycosaminoglycans as a common constituent of all amyloids: or, perhaps amyloid is not a misnomer.

Amyloid is a generic term referring to a group of diseases in which proteinaceous tissue deposits all have in common specific stain affinities, a common appearance in polarized light, common ultrastructure fibrillary characteristics, and uniform x-ray diffraction and infrared spectral properties. Where groups of diseases have a common underlying pathogenetic process the polypeptide responsible for the protein fibril is the same regardless of the specific disease. Where diseases have a different underlying pathogenesis the polypeptide is unique for each disease. The different amyloidogenic polypeptides are clearly not related in terms of amino acid sequence or function, yet they all tend to fold in such a way as to present the same staining, structural or spectral properties. It is proposed that amyloid fibrils are not only composed of the specific amyloidogenic polypeptide but also highly sulphated glycosaminoglycans or proteoglycans which have a profound influence on the manner in which the peptides fold and interact with each other. It is this highly charged carbohydrate which may be common to all amyloids and which plays a determining role in the final appearance of the deposit. Amyloid should therefore be considered as more than simply a protein entity but, as its name originally implied, one related to carbohydrate deposition as well.

Amyloid↗
PubMed2004

Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for beta-amyloid peptide over-production and localization in Alzheimer's disease.

In Alzheimer's disease (AD), the neuropathologic hallmarks of beta-amyloid deposition and neurofibrillary degeneration are associated with early and progressive pathology of the endosomal-lysosomal system. Abnormalities of autophagy, a major pathway to lysosomes for protein and organelle turnover, include marked accumulations of autophagy-related vesicular compartments (autophagic vacuoles or AVs) in affected neurons. Here, we investigated the possibility that AVs contain the proteases and substrates necessary to cleave the amyloid precursor protein (APP) to A beta peptide that forms beta-amyloid, a key pathogenic factor in AD. AVs were highly purified using a well-established metrizamide gradient procedure from livers of transgenic YAC mice overexpressing wild-type human APP. By Western blot analysis, AVs contained APP, beta CTF - the beta-cleaved carboxyl-terminal domain of APP, and BACE, the protease-mediating beta-cleavage of APP. beta-Secretase activity measured against a fluorogenic peptide was significantly enriched in the AV fraction relative to whole-liver lysate. Compared to other recovered subcellular fractions, AVs exhibited the highest specific activity of gamma-secretase based on a fluorogenic assay and inhibition by a specific inhibitor of gamma-secretase, DAPT. AVs were also the most enriched subcellular fraction in levels of the gamma-secretase components presenilin and nicastrin. Immunoelectron microscopy demonstrated selective immunogold labeling of AVs with antibodies specific for the carboxyl termini of human A beta 40 and A beta 42. These data indicate that AVs are a previously unrecognized and potentially highly active compartment for A beta generation and suggest that the abnormal accumulation of AVs in affected neurons of the AD brain contributes to beta-amyloid deposition.

Alzheimer Disease↗
PubMed2005

Overexpression of monocyte chemotactic protein-1/CCL2 in beta-amyloid precursor protein transgenic mice show accelerated diffuse beta-amyloid deposition.

Microglia accumulation at the site of amyloid plaques is a strong indication that microglia play a major role in Alzheimer's disease pathogenesis. However, how microglia affect amyloid-beta peptide (Abeta) deposition remains poorly understood. To address this question, we developed a novel bigenic mouse that overexpresses both amyloid precursor protein (APP) and monocyte chemotactic protein-1 (MCP-1; CCL2 in systematic nomenclature). CCL2 expression, driven by the glial fibrillary acidic protein promoter, induced mononuclear phagocyte (MP; monocyte-derived macrophage and microglial) accumulation in the brain. When APP/CCL2 transgenic mice were compared to APP mice, a fivefold increase in Abeta deposition was present despite increased MP accumulation around hippocampal and cortical amyloid plaques. Levels of full-length APP, its C-terminal fragment, and Abeta-degrading enzymes (insulin-degrading enzyme and neprilysin) in APP/CCL2 and APP mice were indistinguishable. Sodium dodecyl sulfate-insoluble Abeta (an indicator of fibrillar Abeta) was increased in APP/CCL2 mice at 5 months of age. Apolipoprotein E, which enhances Abeta deposition, was also increased (2.2-fold) in aged APP/CCL2 as compared to APP mice. We propose that although CCL2 stimulates MP accumulation, it increases Abeta deposition by reducing Abeta clearance through increased apolipoprotein E expression. Understanding the mechanisms underlying these events could be used to modulate microglial function in Alzheimer's disease and positively affect disease outcomes.

Amyloid beta-Peptides↗
PubMed1998

Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease.

Cerebral amyloid angiopathy in Alzheimer's disease is characterized by deposition of amyloid beta (Abeta) in cortical and leptomeningeal vessel walls. Although it has been suggested that Abeta is derived from vascular smooth muscle, deposition of Abeta is not seen in larger cerebral vessel walls nor in extracranial vessels. In the present study, we examine evidence for the hypothesis that Abeta is deposited in periarterial interstitial fluid drainage pathways of the brain in Alzheimer's disease and that this contributes significantly to cerebral amyloid angiopathy. There is firm evidence in animals for drainage of interstitial fluid from the brain to cervical lymph nodes along periarterial spaces; similar periarterial channels exist in humans. Biochemical study of 6 brains without Alzheimer's disease revealed a pool of soluble Abeta in the cortex. Histology and immunocytochemistry of 17 brains with Alzheimer's disease showed that Abeta accumulates five times more frequently around arteries than around veins, with selective involvement of smaller arteries. Initial deposits of Abeta occur at the periphery of arteries at the site of the putative interstitial fluid drainage pathways. These observations support the hypothesis that Abeta is deposited in periarterial interstitial fluid drainage pathways of the brain and contributes significantly to cerebral amyloid angiopathy in Alzheimer's disease.

Aged↗
PubMed2003

Diverse fibrillar peptides directly bind the Alzheimer's amyloid precursor protein and amyloid precursor-like protein 2 resulting in cellular accumulation.

The Alzheimer's disease Abeta peptide can increase the levels of cell-associated amyloid precursor protein (APP) in vitro. To determine the specificity of this response for Abeta and whether it is related to cytotoxicity, we tested a diverse range of fibrillar peptides including amyloid-beta (Abeta), the fibrillar prion peptides PrP106-126 and PrP178-193 and human islet-cell amylin. All these peptides increased the levels of APP and amyloid precursor-like protein 2 (APLP2) in primary cultures of astrocytes and neurons. Specificity was shown by a lack of change to amyloid precursor-like protein 1, tau-1 and cellular prion protein (PrP(c)) levels. APP and APLP2 levels were elevated only in cultures exposed to fibrillar peptides as assessed by electron microscopy and not in cultures treated with non-fibrillogenic peptide variants or aggregated lipoprotein. We found that PrP106-126 and the non-toxic but fibril-forming PrP178-193 increased APP levels in cultures derived from both wild-type and PrP(c)-deficient mice indicating that fibrillar peptides up-regulate APP through a non-cytotoxic mechanism and irrespective of parental protein expression. Fibrillar PrP106-126 and Abeta peptides bound recombinant APP and APLP2 suggesting the accumulation of these proteins was mediated by direct binding to the fibrillated peptide. This was supported by decreased APP accumulation following extensive washing of the cultures to remove fibrillar aggregates. Pre-incubation of fibrillar peptide with recombinant APP18-146, the putative fibril binding site, also abrogated the accumulation of APP. These findings show that diverse fibrillogenic peptides can induce accumulation of APP and APLP2 and this mechanism could contribute to pathogenesis in neurodegenerative disorders.

Alzheimer Disease↗
PubMed2001

Inhibitors can arrest the membrane activity of human islet amyloid polypeptide independently of amyloid formation.

Human islet amyloid polypeptide (hIAPP), co-secreted with insulin from pancreatic beta cells, misfolds to form amyloid deposits in non-insulin-dependent diabetes mellitus (NIDDM). Like many amyloidogenic proteins, hIAPP is membrane-active: this may be significant in the pathogenesis of NIDDM. Non-fibrillar hIAPP induces electrical and physical breakdown in planar lipid bilayers, and IAPP inserts spontaneously into lipid monolayers, markedly increasing their surface area and producing Brewster angle microscopy reflectance changes. Congo red inhibits these activities, and they are completely arrested by rifampicin, despite continued amyloid formation. Our results support the idea that non-fibrillar IAPP is membrane-active, and may have implications for therapy and for structural studies of membrane-active amyloid.

Amyloid↗