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 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The plasma distribution of gallium (as an analogue of aluminium) was investigated in patients with Alzheimer disease, Down syndrome, or stroke dementia, in subjects on haemodialysis for chronic renal failure, and in healthy controls. Gallium-transferrin binding was significantly lower in the Alzheimer (mean [SEM] 7.9 [1.1]%) and Down syndrome groups (6.9 [0.7]%) than in the controls (17.1 [1.6]%), whereas stroke dementia and haemodialysis patients had normal binding. There were no differences among the groups in plasma citrate concentration. The plasma transferrin concentration was slightly lower in the Alzheimer and Down syndrome groups than in the controls, but even lower in stroke dementia patients (1.74 [0.14] g/l vs 2.98 [0.18] g/l in controls). Transferrin iron saturation was higher in the Alzheimer (58.9%) and Down syndrome groups (81.6%) than in the controls (39.0%) or stroke dementia patients (33.4%). This deficiency of gallium/aluminium binding would leave more unbound aluminium which could move readily into the brain, where it has neurotoxic effects.
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PMID:Defective gallium-transferrin binding in Alzheimer disease and Down syndrome: possible mechanism for accumulation of aluminium in brain. 197 9

The histologically apparent polymorphism of plaques containing beta-amyloid in Alzheimer's disease is thought to represent different stages in plaque evolution. beta-amyloid-immunopositive plaques were classified according to the pattern of beta-amyloid distribution (diffuse vs dense-core) and the presence or absence of dystrophic beta-amyloid precursor protein-immunopositive (beta-APP+) neurites (neuritic vs non-neuritic). The potential contribution of microglia-derived interleukin-1 (IL-1), an immune response cytokine that induces synthesis and processing of beta-APP, to the possible sequential development of these plaque types was examined through determination of the number of IL-1 alpha+ microglia associated with each of four identified plaque types. Diffuse non-neuritic plaques had the least dense and most widely dispersed beta-amyloid, did not exhibit beta-APP+ dystrophic neurites, but most (78%) contained activated IL-1 alpha+ microglia (2 +/- 0.2/plaque; mean +/- SEM). Diffuse neuritic plaques had more dense, but still widely dispersed beta-amyloid, displayed a profusion of beta-APP+ dystrophic neurites, and had the greatest numbers of associated activated IL-1 alpha+ microglia (7 +/- 0.8/plaque). Dense-core neuritic plaques had both compact and diffuse beta-amyloid and had fewer IL-1 alpha+ microglia (4 +/- 0.4/plaque). Dense-core, non-neuritic plaques had compact beta-amyloid, lacked associated diffuse beta-amyloid, and were devoid of both IL-1 alpha+ microglia and beta-APP+ dystrophic neurites. These results suggest an important immunological component in the evolution of amyloid-containing plaques in Alzheimer's disease and further suggest that IL-1-expressing cells are necessary to initiate dystrophic neurite formation in diffuse beta-amyloid deposits.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-1 expression in different plaque types in Alzheimer's disease: significance in plaque evolution. 787 95

Recent experiments have shown that: 1) A chronic 10 month daily administration to rats of the benzodiazepine (BDZ) receptor antagonist, flumazenil (FL; 4 mg/kg in drinking water), from the age of 13 through 22 months, significantly retarded the age-related loss of cognitive functions, as ascertained by the radial arm maze tests conducted two months after FL withdrawal. 2) An equal number of 8 rats died in the control and FL-treated group before the behavioral tests were completed and the animals were sacrificed; the life span of the FL-treated 8 rats equaled 24.0 (+/- 0.6 SEM) months, while that of the control 8 rats equaled 22.3 months (+/- 0.7 SEM), and the group difference was marginally significant (p = 0.04 Mann-Whitney test). 3) In rats sacrificed 3 months after FL withdrawal and behavioral testing, the protective action of FL, relative to age-matched controls, was revealed by a significant reduction in the age-related loss of neurons in the hippocampal formation. 4) In the time period of 3 months between the drug withdrawal and sacrificing of the animals, stress experienced by the aging rats during behavioral testing, related to excessive daily handling of the animals and partial food deprivation to motivate them to perform in the radial arm maze, apparently had excitotoxic effects on the hippocampal neurons, as indexed by the presence of 30% neurons in a state of moderate pyknosis found both in the FL group and the age-matched controls. In the 6 months "young" control group, the number of pyknotic neurons equaled only 3.5%. It was concluded that the drug withdrawal and stress of behavioral testing unleashed the previously FL-controlled age-related degeneration. On the basis of these results and the literature, showing that the tone of the GABAergic system increases with age, and particularly in Alzheimer's disease (AD), the hypothesis of brain aging was formulated. It postulates that in mammals, with growing age, and prematurely in humans with AD, the increasing tone of the BDZ/GABAergic system interferes with antero- and retrograde axonal transport through a chronic depolarizing block of preterminal axon varicosities of the ascending aminergic and cholinergic/peptidergic systems, which are indispensable for normal metabolic/trophic glial-neuronal relationships. Such a state leads to discrete anatomic deafferentation of forebrain systems, and particularly of the neocortex, where block of the anterograde axonal transport results in induction of the cortical mRNA responsible for synthesis of the beta-amyloid precursor protein (beta APP). The simultaneous block of retrograde transport from chronically depolarized preterminal axon varicosities may account for toxic accumulation in cortex of the nerve growth factor (NGF) and other trophins, without which the basal forebrain cholinergic neurons degenerate. The general pharmacologic profile of FL has been discussed on the basis of FL administration to animals and healthy and diseased humans. This profile shows that FL: 1) increases brain metabolic functions; 2) reduces emotional responses, thereby stabilizing the functions of the autonomic system in both humans and animals challenged by adverse environmental stimuli; 3) improves cognitive and coordinated motor functions in both humans and animals; 4) uniquely combines anxiolytic, vigilance and cognitive enhancing, i.e. nootropic, properties, which may, in part, stem from FL-induced emotional imperturbability (ataraxy); 5) facilitates habituation of healthy humans and animals to novel but inconsequential environmental stimuli, and promotes non-aggressive interactions among animals; 6) in single i.v. doses, and administered chronically to humans, FL has antiepileptic actions in the Lennox-Gastaut syndrome and other forms of epilepsy characterized by "spike-and-dome" EEG patterns; these actions are likely to depend on FL's disinhibition of the serotonin system; 7) administered in single i.v...
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PMID:GABAergic deafferentation hypothesis of brain aging and Alzheimer's disease; pharmacologic profile of the benzodiazepine antagonist, flumazenil. 871 36

Our previous studies have implicated perlecan, a specific heparan sulfate proteoglycan, in the pathogenesis of fibrillar beta-amyloid protein (A beta) accumulation and persistence in Alzheimer's disease (AD) brain. In the present investigation, we determined if perlecan mRNA was present in rodent and human brain tissue and whether perlecan persistence in A beta amyloid deposits in AD hippocampus may be partly due to increased perlecan expression and/or decreased perlecan degradation. To detect and to quantify low-abundance perlecan mRNA in rodent and postmortem human brain tissue, regions of perlecan domain I (503 and 366 bp) containing the unique heparan sulfate glycosaminoglycan attachment sites were analyzed by reverse transcription (RT) and polymerase chain reaction (PCR). Perlecan mRNA was detected in rodent brain, kidney, and liver and in human AD and normal aged frontal cortex. Different-size transcripts of perlecan domain I were found, suggesting the existence of alternatively spliced variants of perlecan or closely related gene products. Quantitative competitive RT-PCR using a mutant perlecan domain I internal standard was used to determine perlecan mRNA levels in total RNA isolated from the hippocampus of 10 AD (mean +/- SEM duration of illness, 11.3 +/- 1.4 years) and 10 normal aged controls. No significant difference in perlecan mRNA levels from the hippocampus of AD (1.12 +/- 0.29 amol/500 ng of total RNA) versus normal aged controls (1.09 +/- 0.30 amol/500 ng of total RNA) was found, indicating that perlecan expression remained at steady-state levels. These results therefore suggest that perlecan persistence in A beta-amyloid deposits in late-stage AD may be primarily due to decreased perlecan degradation and removal.
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PMID:Detection and quantitation of perlecan mRNA levels in Alzheimer's disease and normal aged hippocampus by competitive reverse transcription-polymerase chain reaction. 875 20

The neurite extension factor S100 beta is overexpressed by activated astrocytes associated with amyloid-containing plaques in Alzheimer's disease, and has been implicated in dystrophic neurite formation in these plaques. This predicts (a) that the appearance of S100beta- immunoreactive (S100beta+) astrocytes precedes that of dystrophic neurites in diffuse amyloid deposits and (b) that the number of these astrocytes correlates with the degree of dystrophic neurite proliferation in neuritic plaques. As a test of the first prediction, we determined the number of S100beta+ astrocytes associated with different plaque types: diffuse non-neuritic, diffuse neuritic, dense-core neuritic, and dense-core non-neuritic. Diffuse non-neuritic plaques had small numbers of associated S100beta+ astrocytes (1.3 +/- 0.1 S100beta astrocytes per plaque [mean +/- SEM]; 80% of plaques had one or more). These astrocytes were most abundant in diffuse neuritic plaques (4.2 +/- 0.2; 100%), were somewhat less numerous in dense-core neuritic plaques (1.6 +/- 0.2; 90%), and were only rarely associated with dense-core non-neuritic plaques (0.15 +/- 0.05; 12%). As a test of the second prediction, we correlated the number of S100beta+ astrocytes per plaque with the area of beta-amyloid precursor protein (beta-APP) immunoreactivity per plaque (an index of the size of the plaques' dystrophic neurite shells) and found a significant positive correlation (r = 0.74, p < 0.001). This correlation was also evident at the tissue level: the numbers of S100beta+ astrocytes per plaque-rich field correlated with the total area beta-APP immunoreactivity in these fields (r = 0.66, p < 0.05). These correlations support the idea that astrocytic activation and S100 beta overexpression are involved in the induction and maintenance of dystrophic neurites in amyloid deposits, and support the concept of a glial cytokine-mediated cascade underlying the progression of neuropathological changes in Alzheimer's disease.
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PMID:Correlation of astrocytic S100 beta expression with dystrophic neurites in amyloid plaques of Alzheimer's disease. 878 85

DNA damage, as demonstrated by in situ Tdt-mediated dUTP-X-nick end labeling (TUNEL), is widespread in the cerebral cortex in end-stage Alzheimer disease, but has not been previously correlated with stages of neurofibrillary tangle formation. To assess possible relationships between neurofibrillary tangle formation and DNA damage, we used tau immunohistochemistry and TUNEL in tangle-rich fields of tissue sections of subiculum and parahippocampal cortex tissue from 12 Alzheimer and 6 control patients. Structures were classified and quantified as tau-/TUNEL-, tau-/TUNEL+, tau+/TUNEL-, or tau+/TUNEL+. Tau+ structures were subclassified into 4 stages (0-3) based on neurofibrillary tangle morphology. The total number of TUNEL+ neurons was significantly less in control than in Alzheimer patients (35 +/- 7.2 vs 90 +/- 9.3/mm2; mean +/- SEM; p < 0.05). The number of tau+/TUNEL+ neurons (40 +/- 1/mm2) was less than that of tau-/TUNEL- neurons (68 +/- 7/mm2) or tau-/TUNEL+ neurons in the same fields (50 +/- 4/mm2, p < 0.0001). Tau+/TUNEL- structures were fewer in number (21 +/- 1/mm2), with a third of these representing acellular "ghost tangles" (stage 3). Tau+ neurons were more likely than tau- neurons to be TUNEL+ (64 +/- 6% vs 44 +/- 2%; mean +/- SEM; p < 0.01), although most TUNEL+ neurons were tau-, even in these selected, tangle-rich fields. TUNEL positivity was not uniformly distributed among tangle stages. TUNEL positivity was less common among early (stage 0) tangles than in tau neurons (21 +/- 6% vs 44 +/- 2%; p < 0.001), but this rose to 53% among intermediate (stage 1) tangles, and to 87% among late (stage 2) tangles. We suggest that early stages of neurofibrillary tangle formation occur in a subpopulation of relatively healthy (TUNEL-) neurons, and that tangle progression is accompanied by increasing neuronal morbidity.
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PMID:Progressive neuronal DNA damage associated with neurofibrillary tangle formation in Alzheimer disease. 960 Feb 24

Eptastigmine is a new acetylcholinesterase (AChE) inhibitor currently under development for the symptomatic treatment of Alzheimer disease. This study was conducted to establish the maximum tolerated dose and the pharmacodynamics of eptastigmine in nine healthy elderly volunteers. Subjects received single oral doses of 8 mg, 20 mg, 32 mg, and 40 mg eptastigmine and placebo according to a double-blind, randomized, rising-dose, five-way crossover design. Adverse events, blood pressure, heart rate, body temperature, forced expiratory volume, salivary flow, and pupilar activity were closely monitored during treatment. Pharmacodynamic activity of eptastigmine was evaluated with an assay of AChE activity in red blood cells. Eptastigmine doses of 8 mg, 20 mg, and 32 mg were well tolerated. Two of four subjects receiving the 40-mg dose developed profound AChE inhibition (58-59%) and reported severe adverse events (nausea, vomiting, syncope, and bradycardia), precluding further administration in the remaining subjects. Eptastigmine administration produced a weak effect on supine heart rate, body temperature, and pupil diameter. There were no effects on blood pressure, forced expiratory volume, salivary flow, and near point of focus. Acetylcholinesterase activity was inhibited in a dose-related fashion according to a sigmoidal (logistic) function. The mean (+/- SEM) maximum inhibition of AChE activity (Imax) was 14.5+/-3.3%, 20.4+/-2.3%, 28.7+/-2.9%, 45.2+/-1.3% and 53.6+/-2.9% after placebo, 8 mg, 20 mg, 32 mg, and 40 mg of eptastigmine, respectively. The theoretical maximum response (Emax) was 72.9%, and the dose that produced half of the maximum response (ED50) was 29.5 mg. At 24 hours, residual AChE inhibition ranged from 9% to 15%, with a half-life of recovery of the enzyme of approximately 10 hours. The maximum tolerated dose of eptastigmine after single-dose oral administration in healthy elderly subjects is 32 mg. Single oral doses of eptastigmine produce sustained, dose-related inhibition of AChE activity. Adverse events are related to the degree of AChE inhibition.
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PMID:Maximum tolerated dose and pharmacodynamics of eptastigmine in elderly healthy volunteers. 970 45

Previous studies have suggested the involvement of amyloid precursor protein (APP) in Alzheimer's disease (AD), as exons 16 and 17 of the APP gene mutations have been found in some familial AD patients. Furthermore, overexpression and deposition of the beta amyloid peptide, a proteolytic product of APP, have been considered as a pathological hallmark of Alzheimer's disease. Therefore, it is of particular interest to determine the expression of APP gene at the transcription level for better understanding of the roles of APP gene in AD pathogenesis. In this work, we employed the quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) to quantify APP mRNA transcripts in the peripheral mononuclear blood cells (PMBC) of 52 Alzheimer's patients, 28 vascular dementia (VD) patients, and 60 healthy elderly controls. The results showed that the amount (mean +/- SEM) of APP transcripts per microgram of total cDNA was 4.05 +/- 0.27, 2.73 +/- 0.33, and 2.59 +/- 0.27 amole in AD, VD, and healthy controls, respectively. There was a significant increase (P < 0.05) in the expression of APP mRNA transcripts in AD compared with that in VD or in healthy controls. Thus, our data indicated that variation of APP gene expression in PMBC might be a pathogenic source of Alzheimer's disease.
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PMID:Enhanced production of amyloid precursor protein mRNA by peripheral mononuclear blood cell in Alzheimer's disease. 1262 74

Self-assembled amyloid peptide nanotubes (SAPNT) were manipulated and immobilized using dielectrophoresis. Micro-patterned electrodes of Au were fabricated by photolithography and lifted off on a silicon dioxide layer. SAPNT were manipulated by adjusting the amplitude and frequency of the applied voltage. The immobilized SAPNT were evaluated by SEM and atomic force microscopy. The conductivity of the immobilized SAPNT was studied by I-V characterization, for both single SAPNT and bundles. This work illustrates a way to manipulate and integrate biological nanostructures into novel bio-nanoassemblies with concrete applications, such as field-effect transistors, microprobes, microarrays, and biosensing devices.
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PMID:Manipulation of self-assembly amyloid peptide nanotubes by dielectrophoresis. 1913 May 87

Alzheimer's disease (AD), one of the most prevalent neurodegenerative brain diseases, has been extensively researched for years. However, its synaptic structure, which is a basis for understanding neurodegenerative disorders, has not yet been understood clearly. Defining the structures of neurons and their synaptic connections is the significant goal of brain research. To study synaptic connectivity, three-dimensional (3D) reconstructions of the nervous system are very helpful. In this study, the 3D structure of brain synapses in the Drosophila melanogaster Swedish amyloid precursor protein (APP) mutant, which is characterized by early onset AD, was analyzed using focused ion beam/scanning electron microscopy (FIB/SEM). This technique is one of the most useful for 3D reconstruction, as the process of obtaining serial images is fully automated and thus avoids the problems inherent in hand-operated ultrathin serial sectioning. The 3D images of normal and AD brains reported in this study reveal characteristic features of AD such as appearance of autophagy, abnormal axon formation and increased mitochondrial size. This 3D analysis reveals structural change as a basis for understanding neurodegenerative disorder.
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PMID:Ultra-structural analysis of the brain in a Drosophila model of Alzheimer's disease using FIB/SEM microscopy. 2404 68


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