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PubMed1993

Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells.

The cellular mechanism underlying the generation of beta-amyloid in Alzheimer disease and its relationship to the normal metabolism of the amyloid precursor protein are unknown. In this report, we show that 3- and 4-kDa peptides derived from amyloid precursor protein are normally secreted. Epitope mapping and radiolabel sequence analysis suggest that the 4-kDa peptide is closely related to full-length beta-amyloid and the 3-kDa species is a heterogeneous set of peptides truncated at the beta-amyloid N terminus. The beta-amyloid peptides are secreted in parallel with amyloid precursor protein. Inhibitors of Golgi processing inhibit secretion of beta-amyloid peptides, whereas lysosomal inhibitors have no effect. The secretion of beta-amyloid-related peptides occurs in a wide variety of cell types, but which peptides are produced and their absolute levels are dependent on cell type. Human astrocytes generated higher levels of beta-amyloid than any other cell type examined. These results suggest that beta-amyloid is generated in the secretory pathway and provide evidence that glial cells are a major source of beta-amyloid production in the brain.

Amino Acid Sequence↗

PubMed1985

Activities of lysosomal enzymes and levels of serum amyloid A (SAA) in blood plasma of hamsters during casein induction of AA-amyloidosis.

Casein-induced amyloidosis in hamsters was found to be of the AA-type, as shown by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and amino acid analysis of the major low-molecular weight component of the amyloid fibrils. Levels of serum amyloid A (SAA) and the activities of cathepsin D, beta-N-glucosaminidase, serine esterase, lactate dehydrogenase (LDH) and gamma glutamyl transpeptidase (GGT) were measured in the blood plasma during induction of amyloidosis. During the pre-amyloid phase an increase was observed in all these parameters. During the deposition of amyloid, an increase was observed in the activities of the lysosomal enzymes cathepsin D and beta-N-glucosaminidase, which was significantly correlated with amyloid deposition. Serine esterase activities did not show any relationship to amyloid deposition. LDH and GGT activities were normal in the amyloid phase. SAA levels were lower during amyloid deposition than during the pre-amyloid phase. These findings indicate that a specific release of lysosomal contents from mononuclear phagocytic cells is involved in the pathogenesis of AA-amyloidosis. Amyloid deposition may be the result of: (i) extrusion of intralysosomal protein AA or pre-amyloid, followed by extracellular formation of amyloid fibrils; (ii) secretion of lysosomal enzymes, followed by extracellular cleavage of SAA and subsequent aggregation of protein AA with other components.

Amino Acids↗

PubMed1980

Redistribution of amyloid deposits.

After 21 daily subcutaneous injections of 0.5 ml 10% casein, CBA/J mice were left untreated and evaluated periodically for 6 months for the development of amyloid in spleens, livers, and kidneys. At the end of the amyloid-inducing regimen, the mice developed moderate to heavy splenic amyloid, trace to light hepatic amyloid, and virtually no renal amyloid. Renal amyloid appeared about 2 months after cessation of the casein and then increased steadily, while splenic and hepatic amyloid gradually diminished. Six months after the cessation of casein, moderate amyloid deposits were observed in the kidneys whereas no, or only traces of, amyloid remained in spleens and livers. This renal amyloid was localized predominantly in the peritubular area and differed from the renal amyloid seen in rapidly induced disease, when it localizes dominantly in glomeruli. This phenomenon is interpreted in the light of possible redistribution of amyloid deposits from organ to organ, and the clinical and investigative significances of this possibility and others are discussed.

Amyloid↗

PubMed2008

Frequent amyloid deposition without significant cognitive impairment among the elderly.

OBJECTIVE: To characterize the prevalence of amyloid deposition in a clinically unimpaired elderly population, as assessed by Pittsburgh Compound B (PiB) positron emission tomography (PET) imaging, and its relationship to cognitive function, measured with a battery of neuropsychological tests. DESIGN: Subjects underwent cognitive testing and PiB PET imaging (15 mCi for 90 minutes with an ECAT HR+ scanner). Logan graphical analysis was applied to estimate regional PiB retention distribution volume, normalized to a cerebellar reference region volume, to yield distribution volume ratios (DVRs). SETTING: University medical center. PARTICIPANTS: From a community-based sample of volunteers, 43 participants aged 65 to 88 years who did not meet diagnostic criteria for Alzheimer disease or mild cognitive impairment were included. MAIN OUTCOME MEASURES: Regional PiB retention and cognitive test performance. RESULTS: Of 43 clinically unimpaired elderly persons imaged, 9 (21%) showed evidence of early amyloid deposition in at least 1 brain area using an objectively determined DVR cutoff. Demographic characteristics did not differ significantly between amyloid-positive and amyloid-negative participants, and neurocognitive performance was not significantly worse among amyloid-positive compared with amyloid-negative participants. CONCLUSIONS: Amyloid deposition can be identified among cognitively normal elderly persons during life, and the prevalence of asymptomatic amyloid deposition may be similar to that of symptomatic amyloid deposition. In this group of participants without clinically significant impairment, amyloid deposition was not associated with worse cognitive function, suggesting that an elderly person with a significant amyloid burden can remain cognitively normal. However, this finding is based on relatively small numbers and needs to be replicated in larger cohorts. Longitudinal follow-up of these subjects will be required to support the potential of PiB imaging to identify preclinical Alzheimer disease, or, alternatively, to show that amyloid deposition is not sufficient to cause Alzheimer disease within some specified period.

Aged↗

PubMedDate not supplied

Novel glycosaminoglycan precursors as anti-amyloid agents part II.

In vivo amyloids consist of two classes of constituents. The first is the disease defining protein, e.g., A beta in Alzheimer's disease. The second is a set of common structural components that usually are the building blocks of basement membrane (BM), a tissue structure that serves as a scaffold onto which cells normally adhere. In vitro binding interactions between one of these BM components and amyloidogenic proteins rapidly change the conformation of the amyloidogenic protein into amyloid fibrils. The offending BM component is a heparan sulfate (HS) proteoglycan (HSPG), part of which is protein and the remainder a specific linear polysaccharide, which is the portion responsible for binding, and imparting the typical amyloid structure, to the amyloid precursor protein/peptide. Our past work has demonstrated that agents that inhibit the binding between HS and the amyloid precursor are effective anti-amyloid compounds both in vitro and in vivo. The present work is concerned with the design and synthesis of modified sugar precursors of HS, which, when incorporated into the polysaccharide, will alter its structure so that it loses its amyloid precursor protein/peptide-binding and fibril-inducing properties. As part of our continuing study, since our previous report, 17 additional compounds have been designed and synthesized based primarily on the known steps involved in HS biosynthesis. In addition to the 4 reported last year, 10 more have been assessed in tissue culture for their inhibitory effect on heparan sulfate synthesis, and one of these has been assessed for its AA-amyloid inhibitory properties. The majority of the novel sugars are analogues of N-acetylglucosamine. They have been modified either at the 4-OH, 3-OH, or 2-N positions. The majority of the 2-N analogues provide data suggesting that hepatocyte N-demethylases remove the N-substituents converting the 2-N analogues into the natural sugar, a process that dilutes the D-[3H] glucosamine tracer used to track heparan sulfate synthesis and thereby gives the impression that biosynthetic inhibition is occurring. To date 3-deoxy analogues have failed to affect heparan sulfate synthesis significantly. Compounds incorporating the 3,4-dideoxy structural feature are currently being assessed. Using primary hepatocyte cultures, we reported previously that a 4-deoxy analogue is incorporated into HS and terminates its elongation. From the 4-deoxy series, one of the compounds has now been assessed in an in vivo model of AA-amyloid induction. This 4-deoxy analogue inhibited splenic AA amyloid deposition by at least 50%, and liver AA amyloid deposition by 85% when measured as amyloid/unit area of tissue. Furthermore, the spleen weights of the treated group were 1/2-1/3 of that in the untreated group indicating that the total splenic amyloid was 1/4-1/6 of that in the untreated group. The results provide further evidence that heparan sulfate is a critical factor in amyloidogenesis and modifications of sugar precursors of heparan sulfate synthesis may provide leads for therapeutic intervention in amyloidogenesis.

Alzheimer Disease↗

PubMed1983

Frequency and distribution of senile cardiovascular amyloid. A clinicopathologic correlation.

Atrium, ventricle, aorta, lung, kidney, and rectum were removed at autopsy from 85 consecutive elderly patients (aged 80 years or older) and examined for amyloid with Congo red. All tissues containing amyloid were counterstained with an antiserum specific for amyloid fibril protein ASc1 and studied by immunofluorescence. Three distinct forms of amyloid were found: (1) all patients had senile aortic amyloid; (2) 78 percent of patients had isolated atrial amyloid; and (3) 25 percent of patients had senile cardiac amyloid of the ASc1 type. The cardiac amyloid deposits were small and widely scattered in more than 80 percent of patients with isolated atrial amyloid and in more than 50 percent of patients with ASc1-type amyloid. Of 21 patients with ASc1 amyloid, 19 had extracardiac involvement (lung in 81 percent of cases and rectum in 57 percent of cases). The kidney was not involved in any patient. The mean heart weight, frequency of atrial fibrillation, percentage of patients with heart failure, and frequency of myocardial infarction were increased in patients with cardiac amyloid, but these differences failed to reach statistical significance. There was no difference in the mean left ventricular wall thickness or degree of coronary atherosclerosis.

Aged↗

PubMed1992

Serial reconstruction of beta-protein amyloid plaques: relationship to microvessels and size distribution.

The suggestion that the amyloid plaques in Alzheimer disease are formed by abnormal leakage from microvessels is mainly based on the finding that many plaques are topographically associated with microvessels. However, because the microvessel network is dense and amyloid plaques are numerous, the frequently observed association may result from chance contact, especially for larger plaques. Therefore, we determined the frequency of this association as a variable of plaque size. If all the amyloid plaques are associated with microvessels, a constant and high rate of association would be expected for all plaque sizes. On the other hand, if the association is a chance contact, larger plaques would show more frequent contact than smaller ones. Sections were double-immunostained for amyloid plaques and microvessels with antibodies raised against beta-protein and collagen type IV, respectively. Amyloid plaques were reconstructed using 12 serial sections (7 microns thick) from the entorhinal cortex of two Alzheimer patients. With reconstruction we determined the size distribution of amyloid plaques as well as the influence of size on vascular association. All the amyloid plaques larger than 42 microns were associated with microvessels, however, the smaller the amyloid plaques, the less frequently they were associated with microvessels. Interestingly, although diffuse amyloid plaques occur in all size classes, core-containing amyloid plaques have a more discrete size. We conclude that the topographical relationship between amyloid deposition and capillaries does not support the leakage theory for amyloid plaque formation.

Aged↗

PubMed1992

Phosphorylation of Alzheimer amyloid precursor protein by protein kinase C.

The beta/A4 amyloid precursor protein is a membrane protein with one transmembrane domain. The accumulation and deposition of beta/A4 amyloid protein in Alzheimer's disease is thought to be brought about by altered processing of beta/A4 amyloid precursor protein. Activation of protein kinase C and/or inhibition of protein phosphatases 1 and 2A results in an increase in the proteolytic processing and secretion of beta/A4 amyloid precursor protein. These effects might result either from phosphorylation of beta/A4 amyloid precursor protein by protein kinase C or from phosphorylation of components of the beta/A4 amyloid precursor protein processing apparatus. We have previously reported phosphorylation by protein kinase C of a synthetic peptide corresponding to part of the cytoplasmic domain of beta/A4 amyloid precursor protein. However, it was not known whether beta/A4 amyloid precursor protein holoprotein was phosphorylated in its native conformation in the cell membrane. Using a PC12 (rat pheochromocytoma) semi-intact cell system, we now report that mature isoforms of beta/A4 amyloid precursor protein are phosphorylated by protein kinase C at Ser655. Five COOH-terminal fragments which are generated by processing of mature beta/A4 amyloid precursor protein were also phosphorylated by protein kinase C at Ser655. The results support the idea that the beta/A4 amyloid precursor protein haloprotein is a physiological substrate for protein kinase C. These observations should facilitate our understanding of the relationship between altered protein phosphorylation and beta/A4 amyloid production.

Adenosine Triphosphate↗

PubMed2003

Amnesia induced by beta-amyloid fragments is counteracted by cannabinoid CB1 receptor blockade.

Administration of drugs activating cannabinoid CB(1) receptors in the brain induces memory deficit in rodents, and blockade of these receptors may restore memory capacity in these animals. Central administration of beta-amyloid or beta-amyloid fragments may also lead to memory disturbances. This study was undertaken to study the involvement of cannabinoid CB(1) receptors in amnesia induced by beta-amyloid fragments in mice tested in a step-through passive avoidance paradigm. Pre-training intracerebroventricular (i.c.v.) injection of beta-amyloid fragments, beta-amyloid peptide-(25-35) (4, 8 or 16 nmol/mouse) or beta-amyloid peptide-(1-42) (200, 400, 800 pmol/mouse) 7 days prior to the learning trial reduced in a dose-dependent manner the retention of passive avoidance response. This effect was observed in two retention tests, 1 and 7 days after the learning trial. The two beta-amyloid fragments showed similar potency in reducing retention of passive avoidance behavior. This effect was counteracted by a single intraperitoneal (i.p.) injection of the cannabinoid CB(1) receptor antagonist, N-(piperidin-l-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A, 1 mg/kg), made 30 min prior to the second retention test. The injection of SR141716A per se did not affect memory capacity of mice. The i.c.v. administration of beta-amyloid peptide-(25-35) (8 nmol/mouse) or of beta-amyloid peptide-(1-42) (400 pmol/mouse) made 30 min prior to the learning trial failed to affect the retention capacity of mice as measured 1 and 7 days later. Also, the i.p. injection of SR 141716A (1 mg/kg) made 30 min prior to the learning trial did not influence the behavioral response of mice injected with beta-amyloid peptide-(25-35) (8 nmol/mouse) or of beta-amyloid peptide-(1-42) (400 pmol/mouse) 7 days prior to the learning trial. These results show that beta-amyloid fragments induce a dose-dependent memory deficit. Their effect on memory retention depends upon the time of administration and seems to involve cannabinoid CB(1) receptors in the brain.

Amnesia↗

PubMed2005

Effects of ginseng saponins on beta-amyloid-induced amnesia in rats.

We have previously demonstrated that ginseng saponins (GS) can reverse the inhibitory effect of beta-amyloid on acetylcholine (ACh) release in the hippocampal slices. The present study was carried out to examine whether GS has any beneficial effects against amnesia induced by beta-amyloid peptides in vivo. Intracerebroventricular injection of 50 microg, but not 10 microg, beta-amyloid fragment(25-35) markedly impaired the performance of rats in avoiding a shock prod, confirming the amnesiac effect of beta-amyloid. Chronically treating the rats with GS (orally, 5 days before icv beta-amyloid injection and 7 days afterward) resulted in a dose-related improvement against beta-amyloid-induced amnesia; a significant reversion was observed at the highest GS dose (80 mg/kg/day). Post-treatment analysis on K(+)-evoked [(3)H]-ACh release from the hippocampal slices showed that beta-amyloid-treatment significantly reduced ACh release from that of the control group. However, pre-treatment with GS completely protected the animal against beta-amyloid-induced reduction of hippocampal ACh release. In contrast, treating the animals with the same optimal dose of GS and duration but only after icv beta-amyloid injection was found to be ineffective in obliterating beta-amyloid's amnesiac effect. Taken together, these observations indicated that GS pre-treatment can functionally prevent the beta-amyloid-induced memory loss possibly by minimizing the inhibitory effect of beta-amyloid on hippocampal cholinergic transmission.

Acetylcholine↗

PubMed1998

Co-injection of beta-amyloid with ibotenic acid induces synergistic loss of rat hippocampal neurons.

Senile plaques are a pathological hallmark of Alzheimer's disease. The major component of senile plaques is beta-amyloid which consists of approximately 4000 mol. wt of peptide. Accumulating evidence suggests that beta-amyloid may represent the underlying cause of Alzheimer's disease. In vitro, beta-amyloid has been shown either to be directly neurotoxic or to potentiate neurotoxic effects of excitatory amino acids. However, beta-amyloid toxicity in vivo has not always been reproducible. In this study, we injected beta-amyloid fragment 1-40 or 25-35 alone or in combination with a small amount of ibotenic acid, an excitatory amino acid, into rat hippocampus, and examined the histological and immunohistochemical changes two weeks after injection. Although beta-amyloid alone or ibotenic acid alone exerted only minimal degenerating effects on neurons just around the injection site, the co-injection of beta-amyloid 1-40 or beta-amyloid 25-35 with ibotenic acid produced drastic neuronal loss; the haematoxylin-eosin staining revealed that most neurons not only around the injection site but also in distant areas including CA1, CA4 and dentate gyrus were depleted. The neuronal loss occurred in a dose-dependent manner with respect to ibotenic acid. Immunohistochemical analysis showed that beta-amyloid with ibotenic acid induced great depletion of microtubule-associated protein-2 immunoreactivity and infiltration of astrocytes and microglia on neuronal loss. In addition, some apoptotic neuronal death indicated by DNA fragmentation and nucleic condensation was observed. Beta-amyloid depositions detected by two different types of anti-human beta-amyloid antibodies were limited to the injection site. Dizocilpine maleate (MK-801), an antagonist for an excitatory amino acid receptor, completely inhibited the neuronal death in rat hippocampus. These results suggest that the co-injection of beta-amyloid with a small amount of ibotenic acid provides a useful model for investigation of the pathogenetic mechanisms leading to Alzheimer's disease.

Amyloid beta-Peptides↗

PubMed1996

Amyloid probes based on Congo Red distinguish between fibrils comprising different peptides.

BACKGROUND: Amyloid plaques, which characterize degenerating tissue in Alzheimer's disease (brain) and type II diabetes (pancreas), were first visualized by staining with the dye Congo Red (CR). The ability of CR to recognize amyloid fibrils comprising diverse proteins suggests that the binding site includes an unidentified structural feature common to all amyloid fibrils. We set out to design and synthesize analogs of CR that could distinguish between fibrils comprising different peptides. RESULTS: Relative affinities of several CR analogs for two model amyloid fibrils were measured and compared to that of CR. Amyloid fibrils comprising peptides based on the critical carboxyl terminus of the Alzheimer's disease amyloid protein beta1-42 (beta34-42) and the critical region of the type II diabetes pancreatic amyloid protein, IAPP (IAPP20-29) were tested. The ratio of affinities of each individual CR analog for the two amyloid fibrils varied considerably. Complexation of certain metal ions (Cu(II), Zn(II), Ni(II), Cd(II)) by a CR analog did not abolish its affinity for amyloid but changed the affinity ratio significantly. CONCLUSIONS: This study demonstrates that small organic and organometallic molecules are capable of detecting differences in amyloid fibril structure and/or amyloid protein sequence. Molecules of this type could have utility as neuropathological probes or imaging agents, since they are much easier to prepare and functionalize than antibodies and are specific for the fibrillar form of the amyloid proteins.

Amino Acid Sequence↗

PubMed1997

Beta-amyloid neurotoxicity in vitro: evidence of oxidative stress but not protection by antioxidants.

Recent data from several groups suggest that the primary mechanism of beta-amyloid neurotoxicity may be mediated by reactive oxygen species. To evaluate this hypothesis, we first compared the efficacy of antioxidant agents in preventing toxicity caused by oxidative insults (iron, hydrogen peroxide, and tert-butyl hydroperoxide) and beta-amyloid peptides in cultured rat hippocampal neurons. Tested antioxidants (propyl gallate, Trolox, probucol, and promethazine) generally provided significant protection against oxidative insults but not beta-amyloid peptides. Next, we examined whether beta-amyloid causes oxidative stress, by comparing levels of lipid peroxidation after exposure to either iron or beta-amyloid. In a cell-free system, iron but not beta-amyloid generated lipid peroxidation. In culture, both insults caused rapid increases in lipid peroxidation, with iron inducing higher levels at later time points. Pretreatment with the antioxidant probucol significantly reduced lipid peroxidation caused by both insults but only attenuated iron toxicity, suggesting that lipid peroxidation does not contribute directly to cell death induced by beta-amyloid. Finally, we observed that increasing basal levels of oxidative stress by pretreating cultures with subtoxic doses of iron significantly increased neuronal vulnerability to beta-amyloid. The ability of beta-amyloid to induce oxidative stress and the demonstration that oxidative stress potentiates beta-amyloid toxicity support the clinical use of antioxidants for AD. However, these data do not support the theory that the primary mechanism of beta-amyloid toxicity involves oxidative pathways, indicating a continued need to identify additional cellular responses to beta-amyloid that underlie its neurodegenerative actions.

Amyloid beta-Peptides↗

PubMed2006

Regulation of steady-state beta-amyloid levels in the brain by neprilysin and endothelin-converting enzyme but not angiotensin-converting enzyme.

The deposition of beta-amyloid in the brain is a pathological hallmark of Alzheimer disease (AD). Normally, the accumulation of beta-amyloid is prevented in part by the activities of several degradative enzymes, including the endothelin-converting enzymes, neprilysin, insulin-degrading enzyme, and plasmin. Recent reports indicate that another metalloprotease, angiotensin-converting enzyme (ACE), can degrade beta-amyloid in vitro and in cellular overexpression experiments. In addition, ACE gene variants are linked to AD risk in several populations. Angiotensin-converting enzyme, neprilysin and endothelin-converting enzyme function as vasopeptidases and are the targets of drugs designed to treat cardiovascular disorders, and ACE inhibitors are commonly prescribed. We investigated the potential physiological role of ACE in regulating endogenous brain beta-amyloid levels for two reasons: first, to determine whether beta-amyloid degradation might be the mechanism by which ACE is associated with AD, and second, to determine whether ACE inhibitor drugs might block beta-amyloid degradation in the brain and potentially increase the risk for AD. We analyzed beta-amyloid accumulation in brains from ACE-deficient mice and in mice treated with ACE inhibitors and found that ACE deficiency did not alter steady-state beta-amyloid concentration. In contrast, beta-amyloid levels are significantly elevated in endothelin-converting enzyme and neprilysin knock-out mice, and inhibitors of these enzymes cause a rapid increase in beta-amyloid concentration in the brain. The results of these studies do not support a physiological role for ACE in the degradation of beta-amyloid in the brain but confirm roles for endothelin-converting enzyme and neprilysin and indicate that reductions in these enzymes result in additive increases in brain amyloid beta-peptide levels.

Administration, Oral↗

PubMed2005

Advanced glycation end products in intervertebral discs and hip joint capsules: correlation with senile amyloid?

Advanced glycation end-products (AGEs) may be involved in either amyloidogenesis or complications related to amyloid. The incidence of AGE increases with age as does the prevalence of amyloid affecting the hip joint capsule and intervertebral discs. We hypothesized that AGEs may be involved in the pathology of these amyloidoses and investigated the spatial and temporal relationship between AGEs and amyloid of intervertebral discs and hip joint capsules. Using immunohistochemistry, AGEs were found in all 71 intervertebral discs and all 87 hip joint capsules. Amyloid was present in 59 (83%) intervertebral discs and 65 (75%) hip joint capsules. AGEs were found in the immediate vicinity of amyloid deposits in 104 of 253 (41%) investigated amyloid deposits of the intervertebral discs and 159 of 311 (51%) investigated amyloid deposits of the hip joint capsules. However, only rarely were AGEs demonstrated within amyloid deposits. No linear correlation was found between the amount of AGEs and the amount of amyloid deposited. As AGEs are more common than amyloid in intervertebral discs and hip joint capsules, it is conceivable to suggest that AGEs might be involved in the pathogenesis of amyloid at these anatomical sites. However, the amyloid proteins appear not to be modified and AGE modification is not a general characteristic of senile amyloidoses.

Adult↗

PubMed2005

Acceleration of murine amyloidosis by implantation of amyloid-containing grafts.

We examined the transmissibility of amyloidosis by the implantation of amyloid-containing tissue. If the transmissibility similar to prion diseases is applicable, using amyloid-containing tissue for transplantation in humans might be a risk factor. In this study, AA amyloidosis occurred in mice that underwent implantation of AA amyloid-containing grafts to the liver and subsequent inflammatory stimulation. AApoAII amyloidosis occurred after implantation of AApoAII amyloid-containing grafts to the liver or to the subcutaneous space without inflammatory stimulation. Both types of amyloidoses occurred in the recipient mice sooner than expected. Moreover, AA and AApoAII amyloid deposits were found at 12 weeks after implantation in mice given AApoAII amyloid-containing grafts and inflammatory stimulation. These results suggest that implanted amyloid deposits have an AEF effect and that implanted amyloid-containing tissue can promote and accelerate a different type of amyloidosis. In another experiment, mice received amyloid-containing or normal tissue grafts. The degree of amyloid deposition was compared after 6 days and 5 weeks of inflammatory stimulation and when the mice were killed. There was no obvious difference in the degree of amyloid deposition between each group, indicating that the lag-time is shortened by implantation of amyloid-containing tissue, resulting in severe amyloidosis in the short term.

Amyloid↗

PubMed2000

High frequency of amyloid lymphadenopathy in uremic patients.

Amyloid lymphadenopathy has only been reported in case report form, or in small groups of patient groups within large series. We believe that amyloid lymphadenopathy is common in uremic patients, and thus designed this study to determine the frequency of this condition in hemodialysis patients, and to assess its types and patterns. We reevaluated 46 uremic patients' lymph node biopsies for amyloid deposits. We also immunohistochemically identified the protein origin of these deposits using Amyloid A, kappa, lambda, beta2 microglobulin, and transthyretin antibodies. Histopathologically, we observed for vascular involvement, follicular deposition, and diffuse deposition. We detected amyloid deposits in 10 of the 46 (22%) patients' lymph nodes. The patterns of deposition were vascular involvement alone in six specimens, vascular involvement plus follicular deposition in three, and vascular involvement plus diffuse deposition in one specimen. Amyloid AA type protein was present in seven nodes, beta2 microglobulin-related amyloid in two nodes, and immunoglobulin-derived protein (AL) in one node. We assessed these 10 patients for causes of end-stage renal disease (ESRD) and other conditions that might relate to amyloidosis. The cause of ESRD in the seven patients with AA amyloid were renal amyloidosis secondary to Familial Mediterranean Fever in four, glomerulonephritis in one patient who had bronchiectasis and Castleman's disease, unknown in one patient who had bronchial asthma, and pyelonephritis in one patient who had no characteristics that could be linked with AA type amyloidosis. The causes of ESRD in the two individuals with beta2 microglobulin-related amyloidosis who had been on long-term hemodialysis were pyelonephritis and glomerulonephritis. The cause of ESRD in the patient with AL type protein was glomerulonephritis, and this patient had no systemic disease. We conclude that amyloid lymphadenopathy is, indeed, common in uremic patients. Amyloid type AA is the most prevalent form of amyloid protein in uremic patients, but amyloid type does not always correspond with underlying cause of renal failure, or with the presence of systemic disease.

Amyloidosis↗

PubMed2002

Cholesterol and cognition: rationale for the AD cholesterol-lowering treatment trial and sex-related Differences in beta-amyloid accumulation in the brains of spontaneously hypercholesterolemic Watanabe rabbits.

This report presents the scientific rationale and hypothesis for the investigator-initiated, double-blind, placebo-controlled Alzheimer's Disease Cholesterol-Lowering Treatment Trial. As part of the supporting preclinical data, accumulation of neuronal beta-amyloid immunoreactivity was investigated in 12-month-old male spontaneously hypercholesterolemic Watanabe rabbits, female Watanabe rabbits between 3 and >36 months of age, and untreated female New Zealand white rabbits between 6 and 12 months of age. Prior evidence suggests that there are significant accumulations of neuronal beta-amyloid immunoreactivity in the cholesterol-fed New Zealand white rabbit. At 3 months of age, abundant beta-amyloid immunoreactive neurons are also found in female hypercholesterolemic Watanabe rabbits. By 6 months of age, as female Watanabe rabbits are approaching sexual maturity, the number of beta-amyloid immunoreactive neurons was somewhat reduced, but the intensity of the immunoreactivity was clearly and consistently diminished. Very few neurons expressing beta-amyloid immunoreactivity were identifiable among the 12-month-old Watanabe female rabbits. Variably increased numbers of intensely stained beta-amyloid immunoreactive neurons were observed in retired breeder female animals over 3 years of age. Twelve-month-old male Watanabe rabbits exhibited levels of neuronal beta-amyloid immunoreactivity consistent with younger and older female animals, but greater than the adult 12-month-old females. Cholesterol levels in the blood were not noticeably different among females over the age range investigated or compared to 12-month-old males. Estrogen levels varied with age in female Watanabe rabbits in an apparent inverse relationship with neuronal beta-amyloid immunoreactivity. However, there was no evidence of increased neuronal beta-amyloid immunoreactivity in untreated female New Zealand white rabbits with "normal" circulating cholesterol levels at any age investigated. Therefore, under conditions of stable, but elevated, circulating cholesterol levels, pathologic accumulation of neuronal beta-amyloid immunoreactivity was similar in male Watanabe rabbits and female animals prior and subsequent to estrus. The intensity of observable neuronal beta-amyloid immunoreactivity accumulation decreases in female animals as circulating estrogen levels increased with sexual maturity. These data suggest that a loss of circulating estrogen could mark the collapse of a system previously protecting a female from conditions conducive to production of beta-amyloid as a putative neurotoxin in AD. This may, in part, explain the epidemiological evidence for "protective" effects of estrogen in AD.

Alzheimer Disease↗