Journal of Alzheimer's Disease - Volume 3, issue 4

Authors: Stone, T.W. | Behan, W.M.H. | Jones, P.A. | Darlington, L.G. | Smith, R.A.

Article Type: Research Article

Abstract: The kynurenine metabolic pathway from tryptophan accounts for a large proportion of the metabolism of this amino acid in the brain. Although a major route for the generation of the essential co-factor nicotinamide adenine dinucleotide (NAD), two components of the pathway have marked effects on neurons. Quinolinic acid is an agonist at N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors, while kynurenic acid is an antagonist and, thus, a potential neuroprotectant. The levels of quinolinic acid are known to increase substantially following cerebral insults or infection, and has been most clearly implicated in the AIDS-dementia complex. The actions of quinolinic acid and NMDA show …subtle differences, however, which suggest other factors contributing to cell damage. In this article we review the evidence that free radicals may be involved in the neurotoxic effects of quinolinic acid and consider the possibility that quinolinic acid might be involved in Alzheimer's disease. Finally, adenosine receptor ligands can modulate neuronal damage, supporting the view that they may represent suitable targets for the development of novel neuroprotectant drugs for the treatment of Alzheimer's and other neurodegenerative disorders. Show more

Keywords: kynurenines, quinolinic acid, kynurenic acid, neurodegeneration, neuroprotection, tryptophan, purines, adenosine

DOI: 10.3233/JAD-2001-3401

Citation: Journal of Alzheimer's Disease, vol. 3, no. 4, pp. 355-366, 2001

Authors: Hughes, Larry F. | Struble, Robert G. | Shaffer, Carla L.

Article Type: Research Article

Abstract: Objective: To determine the capability of patients with Alzheimer’s disease (AD) and age-matched controls to discriminate and recognize odorants equilibrated for strength and familiarity, and to determine if immediate corrective-feedback can improve performance in either task. Major results: No significant differences between elderly controls (EC) and AD patients were apparent for the discrimination task regardless of feedback condition. The EC group outperformed the AD group on the recognition task. Feedback enhanced EC group performance but failed to benefit the AD group. Conclusions: Early in the disease process, AD subjects have a deficit in processing olfactory cues …at levels beyond that necessary for discrimination. This deficit is specifically related to the olfactory system and is in addition to any general cognitive deficits they may have. Feedback is ineffective for AD subjects but can greatly enhance the performance of the intact elderly on tasks requiring the verbal mediation of olfactory cues. Show more

DOI: 10.3233/JAD-2001-3402

Citation: Journal of Alzheimer's Disease, vol. 3, no. 4, pp. 367-375, 2001

Authors: Ranganathan, Srikanth | Scudiere, Susan | Bowser, Robert

Article Type: Research Article

Abstract: The molecular mechanisms that regulate neuronal cell death in neurodegenerative diseases remain unclear. During neurologic diseases numerous neuronal and glial intracellular signaling pathways are activated by changes within the extracellular environment, which culminate in alterations of nuclear proteins and gene expression. Among the proteins activated or expressed during neurodegenerative diseases include proteins that function during the cell cycle. Early events in cell cycle activation include transition from the G1 to S phase of the cell cycle, which is regulated by the activity of proteins from the retinoblastoma (pRb) and E2F gene families of transcriptional regulators. Hyperphosphorylation of pRb induces the …activation of E2F proteins at the G1-to-S cell cycle transition. Using brain and spinal cord tissues from non-demented control, Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) patients, we identified increased levels of hyperphosphorylated pRb in AD and ALS patients. In addition, we observed altered subcellular distribution of E2F-1 during AD and ALS. Our results suggest that activation and re-distribution of early cell cycle transcriptional regulators occurs in both AD and ALS. Show more

Keywords: Alzheimer's disease, amyotrophic lateral sclerosis, cell cycle, transcription factor, retinoblastoma protein, E2F-1

DOI: 10.3233/JAD-2001-3403

Citation: Journal of Alzheimer's Disease, vol. 3, no. 4, pp. 377-385, 2001

Authors: Ghribi, Othman | DeWitt, David A. | Forbes, Michael S. | Arad, Ayala | Herman, Mary M. | Savory, John

Article Type: Research Article

Abstract: This article has been retracted, and the online PDF has been watermarked “RETRACTED”. A retraction notice is available at DOI: 10.3233/JAD-239015 .

DOI: 10.3233/JAD-2001-3404

Citation: Journal of Alzheimer's Disease, vol. 3, no. 4, pp. 387-391, 2001

Authors: Figueroa, David J. | Shi, Xiao-Ping | Gardell, Stephen J. | Austin, Christopher P.

Article Type: Research Article

Abstract: Amyloid β protein precursor is cleaved by β- and γ-secretases to produce Aβ peptides which deposit in amyloid plaques in Alzheimer's disease (AD) brain. A recently identified beta-site cleaving enzyme (BACE) appears to fulfill the requirements for β-secretase, and presenilin-1 (PS1) appears to constitute the catalytic component of γ-secretase. Each protein has a close homologue (BACE2 and PS2, respectively), whose roles in AβPP cleavage remain uncertain. All four of these genes have been reported to be expressed in the human pancreas, but the cell types expressing these genes remains unknown. We demonstrate here the cell-specific expression of AβPP, BACE, BACE2, …PS1, and PS2 in the human pancreas. The insulin-producing βcells were found to express AβPP, BACE and PS2 at high levels, and PS1 at a lower level. The other islet cell types expressed none of these five genes. By contrast, the exocrine ductal cells of the pancreas expressed AβPP and BACE2 selectively. These results suggest that secretase inhibitors under development for the treatment of AD, particularly those that target BACE, may have potential for adverse effects on pancreatic β cell function, and therefore glycemic control. Show more

DOI: 10.3233/JAD-2001-3405

Citation: Journal of Alzheimer's Disease, vol. 3, no. 4, pp. 393-396, 2001

Authors: Martins, Ralph.N.

Article Type: Article Commentary

DOI: 10.3233/JAD-2001-3406

Citation: Journal of Alzheimer's Disease, vol. 3, no. 4, pp. 397-399, 2001

Authors: Luo, Yuan

Article Type: Research Article

Abstract: An extract of Ginkgo biloba leaves, EGb761, is becoming one of the most popular dietary supplements in the United States to enhance memory. In Europe it is a commonly prescribed drug for treatment of age-related deterioration, including degenerative dementias of the Alzheimer type (AD). Substantial experimental evidence indicates that EGb761 has neuroprotective potency under conditions such as ischemia, seizures and peripheral nerve damage. However, the mechanisms of such neuroprotective effects remain unknown, partially because of the complex chemical composition of EGb761 and the resulting so-called ``polyvalent'' action. This review focuses on cellular and molecular approaches towards understanding the polyvalent action …of EGb761 neuroprotective effect. Two potential mechanisms of action, reducing oxidative damage and stimulating cell survival machinery, are discussed. Better understanding of the neuroprotective mechanisms of EGb761 will provide impetus for possible combination therapies and for the design of rational, ``mechanism-based'' strategies that target age-related neurodegeneration and Alzheimer's disease. Show more

DOI: 10.3233/JAD-2001-3407

Citation: Journal of Alzheimer's Disease, vol. 3, no. 4, pp. 401-407, 2001

Authors: Velez-Pardo, Carlos | Arroyave, Sergio Tobon | Lopera, Francisco | Castaño, Alexandra Duque | Del Rio, Marlene Jimenez

Article Type: Research Article

Abstract: Recently, it has been demonstrated that there is no obvious correlation between DNA fragmentation (according to Terminal dUTP Nick-End Labeling technique) and the severity of amyloid-beta (Aβ) deposition and neurofibrillary tangle (NFT) formation in patients bearing mutations in presenilin 1[E280A]. Indeed, it was observed in 10 out of 48 brain sections TUNEL-positive labeling, while none showed classical apoptotic morphology. Based on these findings, we were interested to determine whether cortical cells from temporal and hippocampus post mortem brain sections die either by an apoptotic or necrotic process in FAD-brain sections labeled TUNEL positive compared with normal brain subjects labeled TUNEL-negative …using electron microscopy (EM). We found that FAD-brain sections labeled TUNEL positive display the typical morphological characteristics of cell death by necrosis i.e. the nuclear chromatin form flocculent aggregates with poorly defined edges and electron lucent (it does not appears black on EM); the chromatin aggregates are irregularly scattered through the nucleus; mitochondria are swoolen with flocculent matrix densities. No apoptotic bodies were observed in any of the brain areas studied. These results may indicate that necrosis is the most generalized cell death process occurring in terminal PS1E280A brains and the DNA fragmentation of nuclei labeled by TUNEL technique may reflect DNA vulnerability. Thus, cell death by necrosis and the accompanying histopathological observations such as severe deposition of amyloid plaques and NFTs, severe gliosis, cortical depopulation, influx of lymphocytes indicative of a chronic inflammation may have an important impact on future therapeutic strategies in the treatment of PS1E280A patients. Show more

Keywords: Alzheimer disease, electron microscopy, necrosis, presenilin 1, PS1[E280A] mutation

DOI: 10.3233/JAD-2001-3408

Citation: Journal of Alzheimer's Disease, vol. 3, no. 4, pp. 409-415, 2001

Authors: Galván, M. | David, J.P. | Delacourte, A. | Luna, J. | Mena, R.

Article Type: Research Article

Abstract: In the present study, neurons of the entorhinal cortex, hippocampus and frontal lobe from non-demented and Alzheimer's disease (AD) cases, were stained in order to study neurofibrillary changes. We have used double immunolabeling with a phosphorylation dependent monoclonal antibody (mAb) to tau, AD2, and the histochemical dye thiazin red (TR). MAb AD2 specifically recognizes phosphorylated Ser396 and Ser404, while TR shows binding sites for amyloid-β and tau when they are in fibrillar states. We show a morphological sequence of changes in the development of neurofibrillary tangles (NFTs), starting from mAb AD2 diffuse labeling in non-NFT bearing cells recognized by mAb …AD2, then going through two subtypes of intracellular NFTs, to a final stage as extracellular-NFTs. Morphometric analysis of the density of AD2 immunoreactive structures showed the NFT density in hippocampus and frontal lobe were the best parameters to differentiate normal aging from AD. Densities of AD2 immunoreactive structures in hippocampus and frontal lobe correlated with the Clinical Dementing Rating score. Based upon the variety of appearances of immunoreactivity displayed by mAb AD2, we were able to stage neurofibrillary changes at the level of individual neurons and brain areas. Our results demonstrate that the intensity of neurofibrillary changes in the hippocampus as well as the extent of the degeneration process in association areas differentiate normal aging from AD, and are well correlated with cognitive impairment. Show more

Keywords: AD2, Alzheimer disease, confocal microscopy, hippocampus, hyperphosphorylated tau protein, neurofibrillary tangles

DOI: 10.3233/JAD-2001-3409

Citation: Journal of Alzheimer's Disease, vol. 3, no. 4, pp. 417-425, 2001

Article Type: Book Review

DOI: 10.3233/JAD-2001-3410

Citation: Journal of Alzheimer's Disease, vol. 3, no. 4, pp. 427-427, 2001