Journal of Alzheimer's Disease - Volume 2, issue 1

Authors: Micic, D.V. | Petronijevic, N.D.

Article Type: Research Article

Abstract: The aim of the present study was to evaluate the acetylcholinesterase activity in the brain of adult gerbils (Meriones unguiculatus) treated with aluminum. AlCl3 × 6H2 O was given “per os” in the amount of 3.7 g/kg body weight. The animals were killed 24, 48, 72 and 96 hours after the treatment. The activities of acetylholinesterase in the mitochondrial and microsomal fractions of cortex, hippocampus and thalamus as well as plasma levels of aluminum were measured. Acetylcholinesterase activity was significantly reduced in the mitochondrial and microsomal fraction of all investigated structures. Decrease of the enzyme activity was observed in …the first 24 hours, and it was most prominent 48 hours after the administration of aluminum in the mitochondrial fractions when the activity of the enzyme was 31%, 29% and 18.9% of the control value, and after 24 hours in the microsomal fractions when the activity of the enzyme was 43%, 48% and 32% of the control value in the cortex, hippocampus and thalamus, respectively. 96 hours after the administration of aluminum the activity of the enzyme was 63%, 57% and 31% of the value in the control group in mitochondrial, and 100%, 80% and 73% of the control value in microsomal fractions in cortex, hippocampus and thalamus. Plasma levels of aluminum were significantly elevated 24 hours after administration of aluminum. After 48 hours the values were doubled in comparison with the control, 72 hours later plasma concentrations of aluminum were decreased, and after 96 hours they reached the value in the control group. We can conclude that a single oral dose (LD50) of aluminum causes the changes in the brain acetylcholinesterase activity. The changes are still present when the aluminum concentration in plasma is normalized. Show more

Keywords: Alzheimer's disease, acetylcholinesterase, aluminum, Mongolian gerbil

DOI: 10.3233/JAD-2000-2101

Citation: Journal of Alzheimer's Disease, vol. 2, no. 1, pp. 1-6, 2000

Authors: Ekinci, Fatma J. | Shea, Thomas B.

Article Type: Research Article

Abstract: Treatment of cultured neurons with ß-amyloid (Aß) evokes multiple consequences, including calcium influx, production of reactive oxygen species (ROS), hyperphosphorylation of tau. Which of these events is the major cause of Aß-induced neurodegeneration has been the subject of controversy. We undertook to determine whether or not the accumulation of hyperphosphorylated tau mediated neurodegeneration. Murine cortical neurons demonstrated increased phospho-tau immunoreactivity between 2–8 hr after treatment of murine cortical neurons with Aß25–35 . Cultures underwent overall neurodegeneration between 8–16 hr as ascertained by phase-contrast microscopy, a commercial “live/dead” assay and externalization of phosphatidyl serine. Unexpectedly, however, the healthiest-appearing neurons in Aß–treated cultures contained …relatively more phospho-tau immunoreactivity, while obviously degenerating neurons contained less; degenerating neurons often contained less phospho-tau immunoreactivity than did non-Aß-treated control neurons. By contrast, accumulation of reactive oxygen species, previously demonstrated to mediate Aß-induced neurodegeneration, was most prominent within visibly-degenerating neurons. These studies do not address the long-term consequences of PHF formation; however, they indicate that tau hyperphosphorylation, although a consequence of Aß treatment, does not directly contribute to acute degeneration of cultured neurons. Show more

Keywords: amyloid, oxidative stress, calcium influx, tau phosphorylation, neurodegeneration, apoptosis, Alzheimer's disease

DOI: 10.3233/JAD-2000-2102

Citation: Journal of Alzheimer's Disease, vol. 2, no. 1, pp. 7-15, 2000

Authors: Andrási, Erzsébet | Farkas, Éva | Gawlik, Dieter | Rösick, Ullrich | Brätter, Peter

Article Type: Research Article

Abstract: Our first project aimed to determine the average values of Fe and Zn in normal German human brain (5 individuals, 10 brain parts). Determinations were carried out by instrumental neutron activation analysis in Berlin. Quality control measurements were performed using National Institute of Standard Technology standard reference materials. The present results show non-homogeneous distribution of Fe and Zn in normal human brain. Our second goal was to study the possible elemental concentration changes in German patients with Alzheimer disease (5 subjects, 10 brain regions). Fe and Zn values are found to be significantly changed in some AD brain regions compared …to the controls. Another object of this work was to extend the method for the determination of elemental concentration not only in whole brain samples (high fat content) but — applying two types of solvent extraction — in lipid fraction and in brain tissue without lipid. Show more

Keywords: Alzheimer disease, iron, zinc, brain regions, instrumental neutron activation analysis

DOI: 10.3233/JAD-2000-2103

Citation: Journal of Alzheimer's Disease, vol. 2, no. 1, pp. 17-26, 2000

Authors: Capellari, Sabina | Zaidi, Syed I.A. | Long, Amy C. | Kwon, Eunice E. | Petersen, Robert B.

Article Type: Research Article

Abstract: The abnormal form of the prion protein has increased resistance to protease digestion and is insoluble in non-ionic detergents. The normal prion protein is modified by the non-obligatory addition of two N-linked glycans. One pathogenic mutation, Thr to Ala at residue 183 of the human prion protein, blocks addition of the first glycan to the Asp residue 181. This mutation has been reported to result in intracellular retention of the mutant protein and its acquisition of pathogenic properties, presumably due to the lack of the glycan. We report that the lack of the N-linked glycan at residue 181 is not …responsible for the block in transport or the acquisition of pathogen-like properties, rather, the Thr to Ala mutation is itself the probable cause of the pathogenic phenotype. Show more

Keywords:

DOI: 10.3233/JAD-2000-2104

Citation: Journal of Alzheimer's Disease, vol. 2, no. 1, pp. 27-35, 2000

Authors: Alafuzoff, Irina | Overmyer, Margit | Helisalmi, Seppo | Soininen, Hilkka

Article Type: Research Article

Abstract: Epidemiological studies have indicated that non-steroidal anti-inflammatory drugs (NSAID) may have some therapeutic effect in Alzheimer's disease (AD) and experimental studies have shown that microglia activation by Aβ-peptide (Aβ) can be influenced by NSAIDs. We analysed 42 clinically and histopathologically verified demented patients fulfilling the histopathological CERAD criteria for definite AD, representing the terminal stage of brain degeneration. Our results indicate that regular NSAID use has a significant influence on the load of Aβ-peptide. Furthermore, our results indicate that regular NSAID use is associated with significantly lower counts of astrocytes and a trend of lower counts of activated microglia …in the brain tissue. The influence of NSAID use was noted in all ApoE genotypes however the trend of lower counts of glial cells with regular NSAID use was more marked in patients carrying the ApoE ε4/4 alleles. Based on our results one would anticipate that regular NSAID dosing could have a beneficial effect on the progression of the disease. However, the fact that we failed to observe significant differences for activated microglia might indicate an age or stage dependent difference in the glial response i.e. in their activation rate. More studies into age and stage related factors influencing the glial response are required if one is to devise novel pharmacological treatment strategies for AD. Show more

DOI: 10.3233/JAD-2000-2105

Citation: Journal of Alzheimer's Disease, vol. 2, no. 1, pp. 37-46, 2000

Authors: Velez-Pardo, C. | Lopera, F. | Jimenez Del Rio, M.

Article Type: Research Article

Abstract: Recent studies have shown that the missense mutation in presenilin-1 [E280A] increases deposition of amyloid-ß (Aß[1-42/43]) producing severe cerebellar pathology. Although Aß has been involved as a neurotoxic peptide, its role in neuronal loss in PS-1 [E280A] patients has not yet been established. This study investigated terminal fluorescein 12-dUTP nick-end labeling (TUNEL)-positive cells (neuron, glia and microglial cells) and thioflavine S-stained Aß-plaques and neurofibrillary tangles in the frontal, parietal, temporal, occipital, hippocampus and cerebellum cortices of 3 normal aging and 8 familial Alzheimer's disease patients with the presenilin-1 [E280A] mutation. Using these approaches, we found no obvious correlation between DNA …fragmentation and the severity of amyloid-ß deposition (Aß) and neurofibrillary tangle (NFT) formation. Indeed, we only observed 10 out of 48 FAD brain sections displaying TUNEL (+) labeling, and none with the classical apoptotic morphology. These results may indicate that DNA fragmentation is not a generalized phenomenon in early-onset FAD PS1 [E280A] patients or that neuronal cells are dying by a different mechanism of cell death. Taking together these findings suggest that Aß and NFTs are not per se a causative factor to damage neuronal cells but their damage could be more related with individual neuronal vulnerability and brain aging Show more

Keywords: Alzheimer disease, amyloid-ß, DNA fragmentation, neurofibrillary tangles, presenilin 1, PS1 [E280A] mutation, TUNEL

DOI: 10.3233/JAD-2000-2106

Citation: Journal of Alzheimer's Disease, vol. 2, no. 1, pp. 47-57, 2000

Authors: Nunomura, Akihiko | Chiba, Shigeru

Article Type: Article Commentary

Abstract: Internucleosomal DNA fragmentation, which is a well-known feature of apoptosis but not an absolute criterion for identifying apoptosis (1), has often been observed in the brain tissue of Alzheimer's disease (AD). However, classical apoptotic morphology such as nuclear condensation, membrane blebbing and apoptotic bodies are seldom seen in AD brain. In this issue of Journal of Alzheimer's Disease, Velez-Pardo et al. have reported the DNA fragmentation using terminal dUTP labeling (TUNEL) in postmortem brains of familial AD with presenilin-1 [E280A] mutation. Importantly, no classical apoptotic morphology has been observed also in the brains of presenilin-1 familial AD. Furthermore, Velez-Pardo et …al. have shown that there is no obvious correlation between DNA fragmentation and the severity of amyloid deposition as well as between DNA fragmentation and the severity of neurofibrillary tangle formation. An apoptotic pathway only takes several hours or at most a few days for completion. In the development of the lateral motor column of the chick embryo, 8,000 cells out of 20,000 cells die, i.e. loss of 40% of the population occurs within 3 days (2). The fact that only 5% of the population in the lateral motor column is undergoing apoptosis at any particular time in this period (2) indicates that apoptotic pathway requires about 10 hours for completion. In a striking contrast with the physiologically programmed cell death, loss of 40% of the population occurs (3,000 neurons out of 7,000 neurons per 50 micron-thick section are lost) within 10 years in the temporal cortex neurons of AD (3). If we suppose that 20 40% of neurons of the temporal cortex are undergoing degeneration at any given time in the course of AD, an individual neuron in the temporal cortex of AD requires 5 – 10 years to die. Indeed, we can observe neurons displaying many of the features of apoptosis in AD. This fact argues that neurons in AD have mounted an effective defense to apoptotic death (an avoidance of apoptosis) rather than actual completion of apoptosis (4,5). It is noteworthy that nucleic acid oxidation occurs widely in vulnerable neuronal populations in AD (6) and oxidative damage can directly cause DNA fragmentation (7). Therefore, DNA damage possibly resulting from oxidative stress involves vulnerable neurons in AD beyond the distribution of amyloid deposition or neurofibrillary tangles, which may be related to neuronal cell death occurring independently of the classical AD pathology (3). Show more

DOI: 10.3233/JAD-2000-2107

Citation: Journal of Alzheimer's Disease, vol. 2, no. 1, pp. 59-60, 2000

Authors: Lucassen, Paul J.

Article Type: Article Commentary

DOI: 10.3233/JAD-2000-2108

Citation: Journal of Alzheimer's Disease, vol. 2, no. 1, pp. 61-67, 2000