Journal of Alzheimer's Disease - Volume 5, issue 2

Authors: García-Sierra, Francisco | Ghoshal, Nupur | Quinn, Bruce | Berry, Robert W. | Binder, Lester I.

Article Type: Research Article

Abstract: The conformation-dependent antibodies Tau-66 and Alz-50 recognize discontinuous epitopes on the tau molecule (residues 155–244 & 305–314 and 5–15 & 312–322, respectively), thereby defining two distinct conformations. In double- and triple-label immunofluorescence experiments we discovered that specific populations of neurofibrillary tangles display either the Alz-50 or the Tau-66 conformation, but not both. In combination with other antibodies to several domains of the molecule we demonstrate that the conformation recognized by Alz-50 seems to be an early event in the formation of neurofibrillary tangles. This conformation is characterized by the presence of predominantly intact N- and C- termini. By contrast, the …Tau-66 conformation is likely a later event in tangle development, being favored in structures containing truncations of both the N- and C- termini. We propose a sequence of events that occurs during the formation and evolution of neurofibrillary tangles based on the initial conformation adopted by tau. In this scheme, the Tau-66 conformation in neurofibrillary tangles may arise from amino and carboxy truncation of tau after it has assumed the Alz-50 conformation. These results indicate that tau structure within the NFT is dynamic in that tau can undergo a "refolding" event following N- and C-terminal truncation. Show more

Keywords: Tau, Alzheimer's disease, pathology, progression, neurofibrillary tangle, truncation

DOI: 10.3233/JAD-2003-5201

Citation: Journal of Alzheimer's Disease, vol. 5, no. 2, pp. 65-77, 2003

Authors: Wong, Boon-Seng | Whiteman, Matthew

Article Type: Article Commentary

Keywords: Tau, Alzheimer's disease, neurodegeneration, protein misfolding

DOI: 10.3233/JAD-2003-5202

Citation: Journal of Alzheimer's Disease, vol. 5, no. 2, pp. 79-80, 2003

Authors: Lahiri, D.K. | Chen, D. | Vivien, D. | Ge, Y.-W. | Greig, N.H. | Rogers, J.T.

Article Type: Research Article

Abstract: One of the major neuropathological characteristics of Alzheimer's disease (AD) is the brain depositions of senile plaques that are mainly composed of toxic amyloid β–peptide (Aβ), which is generated from a family of Aβ containing precursor proteins (AβPP; 695-770 amino acids). The role of cytokines and growth factors has been implicated in the pathogenesis of AD. Our goal is to determine the mode of action of cytokines on the regulation of AβPP gene expression. Here we studied the effect of different cytokines on the activity of 5'-untranslated region (5'-UTR) of AβPP mRNA in human astrocytic cells (U-373). We compared AβPP-5'-UTR …activity in the presence of interleukin-1 (IL-1α and IL-1β), transforming growth factor (TGF-β1) and tumor necrosis factor TNF-α1. The astrocytic cells, which were treated separately with these agents, were transfected with either the vector (pSV2CAT) or pSV2UTR-CAT construct containing 90 bp of AβPP 5'-UTR +54 to 144 bp). This region was cloned upstream of a reporter chloramphenicol acetyl transferase gene (CAT). Our results indicate that the treatment of pSV2UTR-CAT-transfected cells with either IL-1α, IL-1β, TGF-β1 or TNF-α1 stimulated reporter gene activity in a factor-specific manner. This was consistent with their effects on elevating AβPP protein levels. Transfection of the same cells with the pSV2CAT vector lacking 5'-UTR resulted in a reduced reporter gene activity with all treatments studied. DNA-gel shift experiments indicate that the 54/144 region binds to a nuclear protein(s) in a cell type specific manner. These results suggest that 5'-UTR of the AβPP gene can respond to the stimulation of different cytokines, which likely regulate AβPP transcription and translation via regulatory elements present in the AβPP promoter and in 5'-UTR, respectively. The characterization of AβPP regulatory elements, including the 5'-UTR, will accelerate the development of novel agents against new targets for AD. Show more

Keywords: Alzheimer, astrocytoma, beta-amyloid, cytokines, dementia, EMSA, gene regulation, nuclear factor, post-transcription, transcription

DOI: 10.3233/JAD-2003-5203

Citation: Journal of Alzheimer's Disease, vol. 5, no. 2, pp. 81-90, 2003

Authors: Addae, Jonas I. | Youssef, Farid F. | Stone, Trevor W.

Article Type: Research Article

Abstract: Several epidemiological studies have found an association between low educational level (or low cognitively demanding occupations) and dementia. Although other studies have not found evidence to support such an association, there has been a general trend toward a "use it or lose it" concept which attempts to promote a neuroprotective role of intellectual activity against the development of dementia. Formation of amyloid-beta peptide (Aβ) in the brain plays a key role in the development of Alzheimer's disease whilst glutamate has been implicated in the pathophysiology of a number of neurological disorders including Alzheimer's disease and vascular dementia. Aβ can mediate …neurodegeneration by a complex interaction of neurodegenerative processes that involve increasing extracellular concentration of glutamate, increasing intracellular Ca+2 concentration, and apoptosis. Long-term potentiation (LTP, a biological correlate of learning and memory) increases the sensitivity of hippocampal neurons to synaptically released glutamate whilst decreasing responses of neurons to bath applied glutamate receptor agonists and to hypoxia/ischemia in vitro. The effects of LTP are likely to involve changes in intracellular Ca+2 concentration. Based on these findings we are proposing that the LTP-induced neuroprotection in vitro may help explain the epidemiological evidence of a possible neuroprotective role of high intellectual activity against dementia. Show more

DOI: 10.3233/JAD-2003-5204

Citation: Journal of Alzheimer's Disease, vol. 5, no. 2, pp. 91-104, 2003

Authors: Szczepanik, Ann Marie | Ringheim, Garth E.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized by neuropil threads composed of structurally abnormal neurites, neurons containing paired helical filaments of tau protein, and extracellular deposits of amyloid-β (Aβ) peptide, a protein fragment having neurotoxic and glial immune response activating potential. In the present study, we demonstrate that an acute intracerebroventricular (icv) injection of Aβ(1–42) in the mouse induces a time- and dose-dependent production of IL-1α, IL-1β, IL-6 and MCP-1 in the hippocampus and cortex as measured by ELISA. Cytokine and chemokine levels were maximal at 9 h, with MCP-1 and IL-1α remaining elevated over a 24 h period and IL-1β remaining …elevated over a 48 h period. The temporal profile of Aβ-induced cytokine induction differed from that observed for LPS. Following an icv injection of LPS, maximal levels of IL-1α, IL-1β, IL-6 and MCP-1 were attained by 9 h and, except for MCP-1, returned to levels indistinguishable from control at 24 h. MCP-1 remained elevated at 24 h and returned to basal levels at 48 h. In contrast, little production of TNF-α was observed under either Aβ or LPS acute stimulus conditions. Treatment with anti-inflammatory agents such as prednisolone, dexamethasone, or IL-10 inhibited both Aβ- and LPS-induced cytokine and chemokine production in the brain. In summary, icv administration of Aβ and LPS induced elevated brain levels of pro-inflammatory cytokines that could be inhibited by immune suppressing drugs and anti-inflammatory proteins, thus providing support for the utility of anti-inflammatory therapeutics in modulating the immunopathology observed in brain inflammatory diseases such as AD. Show more

DOI: 10.3233/JAD-2003-5205

Citation: Journal of Alzheimer's Disease, vol. 5, no. 2, pp. 105-117, 2003

Authors: Nielsen, Annette Skræp | Ravid, Rivka | Kamphorst, Wouter | Jørgensen, Ole Steen

Article Type: Research Article

Abstract: Apolipoprotein E (APOE) allele ε4 is a risk factor for Alzheimer's disease (AD) and has also been associated with impaired recovery from brain injury. Previous studies on APOE ε4 in dementing disorders other than AD have been rather conflicting, in particular concerning frontotemporal dementia (FTD) and vascular dementia (VD). In the present study we determined APOE genotype in an autopsy series of demented subjects and non-demented controls from the Netherlands Brain Bank. We attempted to create as clear-cut diagnostic groups as possible and paid close attention to AD-type histopathological changes in all cases. In comparison with the APOE ε4 allele …frequency in controls (0.12; n=163 subjects), the APOE ε4 allele frequency was significantly increased in AD (0.42; n=320, p<0.0001), as well as in AD with Lewy bodies (0.43; n=41, p<0.0001) and in demented subjects with no other neuropathological findings than AD-histopathology insufficient for a diagnosis of AD (0.29; n=41, p<0.001). However, the APOE ε4 allele frequency was not significantly increased in FTD (0.18; n=49), VD (0.10; n=20) or in Lewy body disease without concomitant AD changes (0.13; n=12). As concerns dementing disorders, our results suggest that APOE ε4 is selectively associated with the presence of AD-type histopathology. Show more

DOI: 10.3233/JAD-2003-5206

Citation: Journal of Alzheimer's Disease, vol. 5, no. 2, pp. 119-125, 2003

Authors: Lee, Ming-Sum | Tsai, Li-Huei

Article Type: Research Article

Abstract: The relationship between amyloid plaques and neurofibrillary tangles, the two pathologic hallmarks of Alzheimer's disease (AD), is an unknown and controversial subject. However, emerging evidence from genetic and biochemical studies suggests that accumulation of amyloid β peptides may play a causative role in AD pathogenesis. This led to the amyloid hypothesis, which proposes that amyloid β peptides disrupt neuronal metabolic and ionic homeostasis and cause aberrant activation of kinases and/or inhibition of phosphatases. The resulting alteration in kinase and phosphatase activities ultimately leads to hyperphosphorylation of tau and formation of neurofibrillary tangles. Cyclin-dependent kinase 5 (Cdk5) is a tau kinase …whose activity is induced by amyloid β peptides. Its deregulation may represent one of the signal transduction pathways that connect amyloid β toxicity to tau hyperphosphorylation. This article reviews the functions and regulation of Cdk5. Evidence that suggests deregulation of Cdk5 activity in AD by virtue of calpain cleavage of its activator p35 to p25 will be discussed. Show more

DOI: 10.3233/JAD-2003-5207

Citation: Journal of Alzheimer's Disease, vol. 5, no. 2, pp. 127-137, 2003

Authors: Ma, Qiu-Lan | Chan, Piu | Yoshii, Mitsunobu | Uéda, Kenji

Article Type: Research Article

Abstract: α-Synuclein is a neuronal protein originally identified in Alzheimer's disease (AD) amyloid plaques in 1993 and named non-Aβ component precursor (NACP) [92]. Later, the discovery of two missense mutations (G88C and G209A), which resulted in Ala30Pro (A30P) and Ala53Thr (A53T) substitutions, of the α-synuclein gene in certain autosomal-dominant early onset familial Parkinson's disease (PD) has greatly promoted the understanding of the role of α-synuclein in the pathogenesis of neurodegenerative diseases, such as PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) [5,6,51,75]. At present, it is widely accepted that α-synuclein may play a central role in several neurodegenerative …disorders because of the presence of insoluble α-synuclein as the major fibrillar component of inclusion bodies. From the cloning of the human α-synuclein cDNA in 1993 to the present, α-synuclein has been carefully documented in many aspects. In this article, we review the progress of studies on α-synuclein and its role inα-synuclein-related neurodegenerative diseases. Show more

DOI: 10.3233/JAD-2003-5208

Citation: Journal of Alzheimer's Disease, vol. 5, no. 2, pp. 139-148, 2003

Authors: Jahroudi, Nadia | Schmaier, Alvin | Srikanth, Sujata | Mahdi, Fakhri | Lutka, Frances A. | Bowser, Robert

Article Type: Research Article

Abstract: Dysfunction of brain vascular endothelial cells may be associated with the pathogenesis of several diseases including cerebral amyloid angiopathy, hemorrhagic stroke and Alzheimer disease. New model systems are necessary to examine the contribution of brain endothelial cells in these disorders. The Von Willebrand factor gene promoter fragment that spans sequences -487 to +247 targets the expression of LacZ marker gene in transgenic mice specifically to brain vascular endothelial cells. Transgenic mice have been prepared that express human amyloid β protein precursor protein (AβPP) isoforms 695 and 751 (wild-type and Dutch variant mutations) under the regulation of this VWF promoter sequence. …These AβPP transgenes are specifically expressed in brain vascular endothelial cells. The VWF promoter is a valuable tool for targeting gene expression to brain vascular endothelial cells to provide a model to directly examine endothelial cell placement of genes and their contribution to cerebral vascular disease. Show more

Keywords: amyloid β-protein precursor, von Willebrand factor promoter, transgenic mice, cerebral amyloid angiopathy, endothelial cells

DOI: 10.3233/JAD-2003-5209

Citation: Journal of Alzheimer's Disease, vol. 5, no. 2, pp. 149-158, 2003

Article Type: Book Review

DOI: 10.3233/JAD-2003-5210

Citation: Journal of Alzheimer's Disease, vol. 5, no. 2, pp. 159-160, 2003