Searching for just a few words should be enough to get started. If you need to make more complex queries, use the tips below to guide you.
Purchase individual online access for 1 year to this journal.
Price: EUR 595.00Impact Factor 2024: 3.4
The Journal of Alzheimer’s Disease is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer’s disease.
The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer’s disease.
Authors: Lasn, Helen | Winblad, Bengt | Bogdanovic, Nenad
Article Type: Research Article
Abstract: The nuclei of the olivary complex are involved in regulating motor movements and in motor learning. Aging is characterized by a progressive accumulation of lipofuscin while the number of olivary neurons is unchanged. It is not known whether neuronal loss occurs in the olivary nucleus during Alzheimer's disease (AD). The aim of this study was to estimate the total number of neurons in the principal olivary nucleus (PO) in AD and control brains using an optimized design for sampling and an unbiased stereological method called the optical fractionator. This study was based on 13 control (mean age = 57 y, …range 17–95 y) and 16 AD brains (mean age = 86 y, range 67–93 y). Using paraffin-embedded, Nissl-stained sections for quantification, we found a significant difference between the mean values (mean ± SD) of the AD group vs. aged-matched controls (4.3 × 105 ± 1.1 vs. 6.53 × 105 ± 1.39 p < 0,003). There was no significant difference between younger controls vs. older controls (7.1 × 105 ± 1.5 vs. 6.5 × 105 ± 1.4 p = 0.76). While there was no neuronal loss in normal aging, in AD the PO is characterized by a significant neuronal loss up to 34%. can occur in regions devoid of neurofibrillary changes. Show more
Keywords: unbiased quantification, dementia, human brain, neuronal loss
DOI: 10.3233/JAD-2001-3201
Citation: Journal of Alzheimer's Disease, vol. 3, no. 2, pp. 159-168, 2001
Authors: Gu, Yaping | Jing, Yi | Kumar, Anil | Sharma, Yogesh | Fujioka, Hisashi | Singh, Neena
Article Type: Research Article
Abstract: Prion diseases or transmissible spongiform encephalopathies, are neurodegenerative disorders that are genetic, sporadic, or infectious. The pathogenetic event common to all prion disorders is the conformational transformation of the cellular prion protein (PrPC ) to the scrapie form (PrPSc ), that deposits in the brain parenchyma and induces neuronal death. Infectious prion disorders are caused by exogenously introduced PrPSc that acts as a template in the conversion of endogenous PrPC to nascent PrPSc , and subsequently the process becomes autocatalytic. To understand the process of cellular uptake of PrPSc and its mechanism of cellular toxicity, previous studies …have used a PrP fragment spanning residues 106-126 (PrPTx ) that is toxic to primary neurons in culture, and mimics PrPSc in its biophysical properties [9,11,14]. Several possible mechanisms of cell death by PrPTx have been proposed [2,3,10,11,18], but the existing data are unclear. To identify the biochemical pathways of neurotoxicity by this fragment, we have isolated mutant neuroblastoma and NT-2 cells that are resistant to toxicity by PrPTx . We show that these cells bind and internalize PrPTx in a temperature dependent fashion, and the peptide accumulates in intracellular compartments, probably lysosomes, where it has an unusually long half-life. The PrPTx -resistant phenotype of the cells reported in this study could result from aberrant binding or internalization of the peptide, or due to an abnormality in the downstream pathway(s) of neuronal toxicity. The PrPTx -resistant cells are therefore a useful tool for evaluating the cellular and biochemical pathways that lead to cell death by this peptide, and will provide insight into the mechanism(s) of neurotoxicity by PrPSc . Show more
Keywords: prion, toxic peptide, resistant cells
DOI: 10.3233/JAD-2001-3202
Citation: Journal of Alzheimer's Disease, vol. 3, no. 2, pp. 169-180, 2001
Authors: Pellegrini, Luca | Passer, Brent J. | Canelles, Matilde | Lefterov, Ilyia | Ganjei, J. Kelly | Fowlkes, B.J. | Koonin, Eugene V. | D'Adamio, Luciano
Article Type: Research Article
Abstract: The familial Alzheimer's disease gene products, presenilin-1 and presenilin-2 (PS1 and PS2), are involved in amyloid β-protein precursor processing (AβPP), Notch receptor signaling, and programmed cell death. However, the molecular mechanisms by which presenilins regulate these processes remain unknown. Clues about the function of a protein can be obtained by seeing whether it interacts with another protein of known function. Using the yeast two-hybrid system, we identified two proteins that interact and colocalize with the presenilins. One of these newly detected presenilin-interacting proteins belongs to the FtsH family of ATP-dependent proteases, and the other one belongs to Rhomboid superfamily of …membrane proteins that are highly conserved in eukaryotes, archaea and bacteria. Based on the pattern of amino acid residues conservation in the Rhomboid superfamily, we hypothesize that these proteins possess a metal-dependent enzymatic, possibly protease activity. The two putative proteases interacting with presenilins could mediate specific proteolysis of membrane proteins and contribute to the network of interactions in which presenilins are involved. Show more
Keywords: presenilin, AβPP, Alzheimer's disease, Rhomboid, metalloprotease
DOI: 10.3233/JAD-2001-3203
Citation: Journal of Alzheimer's Disease, vol. 3, no. 2, pp. 181-190, 2001
Authors: Wolozin, Benjamin
Article Type: Research Article
Abstract: Presenilins were originally identified because they cause a neurodegenerative disease, but the impact of these proteins on the neuron appears to extend beyond neurodegeneration and into fundamental concepts of cell biology and development. Presenilins were identified as a result of the steady march of molecular genetics which first lead to identification of loci on chromosomes 1 and 14 that segregated with the phenotype of early onset familial Alzheimer Disease (AD), and then to discovery of the genes coding for PS1 and PS2.
DOI: 10.3233/JAD-2001-3204
Citation: Journal of Alzheimer's Disease, vol. 3, no. 2, pp. 191-193, 2001
Authors: Tomashevski, Andrei | Husseman, Jacob | Jin, Lee-Way | Nochlin, David | Vincent, Inez
Article Type: Research Article
Abstract: The cdc2/cyclin B1 kinase is absent from neurons that are terminally differentiated. However, unscheduled activation of Cdc2/cyclin B and accumulation of mitotic phosphoepitopes have been described in degenerating neurons of Alzheimer's disease (AD), and their appearance precedes hallmark lesion formation. In cycling cells the timing of cdc2 activation and onset of mitosis are determined by the Wee1 tyrosine kinase. We therefore investigated the Wee1 kinase in human brain. Surprisingly, we have found that the enzyme is constitutively active in neurons of normal brain. Consistent with its behavior in M phase, Wee1 in AD has decreased activity, becomes MPM-2 immunoreactive, and …is redistributed from its normally nuclear domain to the cytoplasm of affected neurons. These data suggest that Wee1 functions in normal postmitotic neurons, but is altered in AD so as to promote activation of Cdc2/cyclin B1. Thus, Wee1 is yet another mitotic regulator that participates in the AD neurodegenerative process. Show more
DOI: 10.3233/JAD-2001-3205
Citation: Journal of Alzheimer's Disease, vol. 3, no. 2, pp. 195-207, 2001
Authors: Fonte, Justin | Miklossy, Judith | Atwood, Craig | Martins, Ralph
Article Type: Research Article
Abstract: The most consistent diagnostic neuropathological lesion in Alzheimer's disease (AD) is the senile plaque of which the 4 kD amyloid-β (Aβ) peptide is the major proteinaceous component. In this study cortical Aβ levels were immunochemically measured in 70 post-mortem human brains and compared against their neuropathological grading as determined by the densities of amyloid plaques and neurofibrillary tangles. The mean concentration of cortical Aβ/mg protein increased with the severity of the cortical degenerative changes (AD0 < AD1 < AD2 < AD3). Brains with the severe degenerative changes (AD3), corresponded to definite AD cases and exhibited significantly increased concentrations of Aβ …(11.1 ± 3.08 ng/mg total protein, n=17) when compared with control brains without any degenerative changes (AD0; 0.06 ± 0.06 ng/mg total protein, n=14, P=0.003). The extraction of Aβ from the cortex of AD3 brains was significantly enhanced in a dose dependent manner by the presence of the metal ion chelator N,N,N',N'-tetrakis(2-pyridylmethyl) ethylenediamine (5 mM TPEN, P < 0.0001). The chelator/antioxidant 1,2-dithiolane-3-pentanoic acid (lipoic acid), also resolubilized Aβin a dose-dependant manner. Both chelators also enhanced the extraction of Aβ from the frontal cortex of AβPP-transgenic mice suggesting this animal model of amyloidosis may be useful for evaluating the biochemical and therapeutic effects of chelators/antioxidants on Aβ deposition. In summary our results indicate that increased Aβ load is correlated with the severity of the cortical AD-type changes and that chelators/antioxidants may be useful in reducing neuronal amyloid burden. Show more
DOI: 10.3233/JAD-2001-3206
Citation: Journal of Alzheimer's Disease, vol. 3, no. 2, pp. 209-219, 2001
Authors: Buxbaum, Joseph D. | Geoghagen, Neil S.M. | Friedhoff, Lawrence T.
Article Type: Research Article
Abstract: Epidemiological studies have demonstrated that hypercholsterolemia is a significant risk factor for Alzheimer's disease (AD). The mechanism by which increased cholesterol may contribute to AD is unknown. However, as the generation and accumulation of the amyloid Aβ peptide in the brain appears to be significant for the initiation and progression of AD, it is possible that cholesterol levels can regulate Aβ formation and/or clearance. To test the effects of altering cholesterol on Aβ formation, we incubated cells in the presence of lipid depleted serum, with or without the active metabolite of the HMG-CoA reductase inhibitor lovastatin. After confirming that cholesterol …was depleted in the cells, we then measured the fraction of Aβ formed from its precursor βPP under each condition. We observed that cholesterol depletion led to a profound decrease in the levels of Aβ released from the cells. This effect of lovastatin acid was observed at concentrations of 0.05–5 μM, ranges where this compound is effective at inhibiting HMG-CoA reductase, thereby inhibiting cholesterol synthesis. In contrast, the release of an additional AβPP fragment, AβPPs, was only modestly reduced by cholesterol treatment. In further studies, we determined that the decreased release of Aβ was not due to its accumulation in the cell, but rather due to decreased formation of Aβ. Finally, we were able to exclude decreased maturation (glycosylation and sulfation) of newly synthesized AβPP as a cause for the effects of lovastatin acid on βPP processing and Aβ formation. Our results demonstrate that reducing cellular cholesterol by the use of an HMG-CoA reductase inhibitor regulates Aβ formation. This effect may involve alterations in the trafficking of AβPP and/or alterations in the activity of the proteases that cleave AβPP. The results suggest a mechanism by which hypercholesterolemia may increase risk for AD and indicate that reduction in cholesterol may delay the onset and/or slow the progression of AD. Show more
DOI: 10.3233/JAD-2001-3207
Citation: Journal of Alzheimer's Disease, vol. 3, no. 2, pp. 221-229, 2001
Authors: Chui, D.H. | Dobo, E. | Makifuchi, T. | Akiyama, H. | Kawakatsu, S. | Petit, A. | Checler, F. | Araki, W. | Takahashi, K. | Tabira, T.
Article Type: Research Article
Abstract: It is widely accepted that Aβ plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) [27]. Attention has been focused mainly on how extracellular Aβ exerts its effects on neuronal cells [7,11,16,32]. However, neuronal degeneration from an accumulation of intracellular Aβx-42 (iAβ42) occurs in presenilin 1 (PS1) mutant mice without extracellular Aβ deposits [5]. In the present study, intracellular deposits of iAβ42 are correlated with apoptotic cell death in AD and PS-1 familial AD (PS1 FAD) brains by means of triple staining with antibodies to Aβ, TUNEL, and staining with Hoechst 33342. Neurons simultaneously positive for iAβ42 and …the TUNEL assay were significantly more abundant in AD brains than in controls. The number of apoptotic neurons with intracellular neurofibrillary tangles (iNFTs) was insignificant. Our results indicate that intraneuronal deposition of a neurotoxic form of Aβseems to be an early event in the neurodegeneration of AD. Show more
DOI: 10.3233/JAD-2001-3208
Citation: Journal of Alzheimer's Disease, vol. 3, no. 2, pp. 231-239, 2001
Authors: Tekirian, Tina L.
Article Type: Research Article
Abstract: The assessment of protein or amino acid variations across evolution allows one to glean divergent features of disease-specific pathology. Within the Alzheimer's disease (AD) literature, extensive differences in Aβ processing across cell lines and evolution have clearly been observed. In the recent past, increased levels of amyloid β Aβ1-42 have been heralded to be what distinguishes whether one is prone to the development of AD [59]. However, observations in naturally occurring, non-transgenic animals which display a great deal of parenchymal Aβ1-42 (Aβ found within extracellular plaque deposits) and a complete lack of β1-40 within these same Aβ1-42 plaques raise the …issue of whether Aβx-42 (Aβ that is truncated or modified at the N- terminus), rather than Aβ1-42, is instead the critical mediator of Aβ production and pathogenesis [47,49]. Distinct ratios of Aβ N-terminal variants (i.e. Aβ1-x, Aβ3-x, Aβ11-x, β17-x) have been assessed in human amyloid plaques [18,21,40,41,42,47,48,49,52]. Moreover, ratios of specific Aβ N-terminal variants separate naturally occurring, non-transgenic animals which develop abundant levels of Aβx-42 and not Aβx-40 from human AD participants who harbor plaques that contain both the Aβx-42 and Aβx-40 variants [49]. Next, Teller and colleagues have demonstrated the presence of N-terminal truncated soluble 3kD (likely Aβ17-x) and 3.7kD peptides (in addition to 4kD Aβ) well before the appearance of amyloid plaques in Down Syndrome brain [51], indicating an early contribution of the β N-terminus to the formation of amyloid pathology. Additional critical facts concerning the major contribution of the Aβ N-terminus in AD pathogenesis include observations which support thatβ generated by rodent neurons is predominantly truncated at Aβ11-x [13], the major form of APP C-terminal fragments in mice lacking functional PS1 is AβPP11-98 [9], β11-x expression is increased as a function of BACE expression [55], and an interrelationship between presenilin-1 mutations and increased levels of N-terminally truncatedβ [40]. This commentary highlights current understanding and potential biochemical, pathological, and cell biological contributions of Aβ N-terminal variants implicated during the course of AD pathogenesis. Although the amyloid β protein precursor (AβPP) gene and Aβ are highly conserved across mammalian species, there are species-specific differences. For instance, the primate, guinea pig, canine, and polar bear share an identical Aβ sequence to that observed in human brain while the rat displays a distinct amino acid sequence with substitutions at residues 5 (Arg), 10 (Tyr), and 13 (His) [24,37]. All of these mammals generate Aβ1-42 via cleavage by at least two enzymes, beta (β-) secretase and gamma (γ-) secretase (Fig. 1). The enzyme that liberates the N- terminus of the Aβ peptide (`β-secretase') is also termed BACE (beta-site AβPP cleaving enzyme) [55]. Cathepsin D, which accumulates within AD neurons [15], also cleaves at the N-terminal side of the first aspartate residue of amyloid β [2]. β-secretase activity is necessary in order to initiate 4kD β1-x formation by cleaving AβPP at the N-terminus and results in the release of a soluble 100kD AβPP N- terminal fragment and a 12kD membrane bound C-terminal fragment (C99/C100) [55]. The carboxyl-terminus of the Aβpeptide is liberated through cleavage by the enzyme termed γ-secretase. In the past, potential AD therapeutic strategies have mainly been geared towards gamma-secretase inhibition. However, such strategies alone no longer appear sound as it is clear that the AβPP C99/C100 fragment itself, which requires β-, but not γ-, secretase cleavage for generation and includes the entire Aβ peptide, is neurotoxic when evaluated in cultured cells [12,30,34]. Thus, γ-secretase inhibition alone would not preclude the generation of the neurotoxic C99/C100 fragment. Show more
DOI: 10.3233/JAD-2001-3209
Citation: Journal of Alzheimer's Disease, vol. 3, no. 2, pp. 241-248, 2001
Authors: Trojanowski, J.Q.
Article Type: Research Article
Abstract: The National Institute on Aging (NIA) of the National Institutes of Health (NIH) has stimulated many recent landmark advances in the understanding and treatment of Alzheimer's disease (AD) and related dementing disorders. This progress is due in part to an extramural network of AD Centers (ADCs) that was established 15 years ago as a component of the NIA Dementias of Aging Program. The ADCs provide a unique infrastructure to support and augment studies on the pathobiology of AD and related disorders as well as to educate scientists and the public about these neurodegenerative dementias. The mission and structure of the …ADC network are summarized to illustrate how the ADCs play important roles in accelerating development of effective therapies for AD and related disorders. Show more
Keywords: Alzheimer's disease, neurodegenerative dementias
DOI: 10.3233/JAD-2001-3210
Citation: Journal of Alzheimer's Disease, vol. 3, no. 2, pp. 249-251, 2001
Article Type: Book Review
DOI: 10.3233/JAD-2001-3211
Citation: Journal of Alzheimer's Disease, vol. 3, no. 2, pp. 253-254, 2001
Authors: Flood, Dorothy G.
Article Type: Obituary
DOI: 10.3233/JAD-2001-3212
Citation: Journal of Alzheimer's Disease, vol. 3, no. 2, pp. 255-255, 2001
IOS Press, Inc.
6751 Tepper Drive
Clifton, VA 20124
USA
Tel: +1 703 830 6300
Fax: +1 703 830 2300
sales@iospress.com
For editorial issues, like the status of your submitted paper or proposals, write to editorial@iospress.nl
IOS Press
Nieuwe Hemweg 6B
1013 BG Amsterdam
The Netherlands
Tel: +31 20 688 3355
Fax: +31 20 687 0091
info@iospress.nl
For editorial issues, permissions, book requests, submissions and proceedings, contact the Amsterdam office info@iospress.nl
Inspirees International (China Office)
Ciyunsi Beili 207(CapitaLand), Bld 1, 7-901
100025, Beijing
China
Free service line: 400 661 8717
Fax: +86 10 8446 7947
china@iospress.cn
For editorial issues, like the status of your submitted paper or proposals, write to editorial@iospress.nl
如果您在出版方面需要帮助或有任何建, 件至: editorial@iospress.nl