Journal of Alzheimer's Disease - Volume 6, issue 6

Authors: Jordá, E.G. | Verdaguer, E. | Jiménez, A. | Canudas, A.M. | Rimbau, V. | Camps, P. | Muñoz-Torrero, D. | Camins, A. | Pallàs, M.

Article Type: Research Article

Abstract: Acetylcholinesterase inhibitors (AChEI) are among the drugs most widely used in the treatment of Alzheimer's disease. They increase the levels of acetylcholine and thus improve the cognitive symptoms that are impaired. We tested whether specific AChEI show additional neuroprotective properties against colchicine-induced apoptosis in cerebellar granule neurons (CGNs), a well established apoptotic model mediated by neuronal cytoskeleton alteration. Colchicine-induced apoptosis is due to an increase in the activity of GSK-3β and CDK5, two enzymes involved in cytoskeletal alteration. Furthermore, the intrinsic apoptotic pathway is activated by colchicines, as revealed by cytochrome c release and Bax translocation. Tacrine, (-)-huperzine A and …(±)-huprine Y, the AChEI tested in the study, did not reverse the loss of neuronal viability induced by colchicine. Moreover, the increase in apoptotic features induced by colchicine treatment, as measured by flow cytometry and nuclear chromatin condensation, was not prevented by these AChEI. Although some of these drugs are of interest to treat Alzheimer's disease, their lack of efficacy in the prevention of colchicine-induced apoptosis in CGNs suggests that they cannot prevent neuronal loss due to cytoskeleton alteration. Show more

Keywords: acetylcholinesterase inhibitors, neuronal death, colchicine, cerebellar granule cells, rat

DOI: 10.3233/JAD-2004-6601

Citation: Journal of Alzheimer's Disease, vol. 6, no. 6, pp. 577-583, 2004

Authors: Sabbagh, Marwan | Zahiri, H. Reza | Ceimo, Joanne | Cooper, Kimbal | Gaul, William | Connor, Donald | Sparks, D. Larry

Article Type: Research Article

Abstract: Objective: To characterize the lipid profile in Alzheimer's Disease (AD) and to determine whether it differs from the cardiac risk profile. Background: Links between hypercholesterolemia and AD development continue to grow. Presently, limited information exists about the lipid profile characteristics in AD. Methods: We examined the lipid profiles (total cholesterol (TC), high-density lipoprotein (HDL), lower-density lipoprotein (LDL), TC/HDL ratio, and triglyceride (TG) levels) of 153 subjects with probable/possible AD (mean age 77.2 ± 8.6 years, mean MMSE 19.9 ± 5.6) and 25 non-demented subjects with atherosclerotic heart disease (ASHD) (mean age 73.8 ± 7.2 years); neither …on lipid lowering therapy. Results: Subjects with TC > 200 mg/dl composed 69% of AD and 72% of ASHD groups. Mean TC was 218.9 ± 38.9 mg/dl and 218.5 ± 9.2 mg/dl for AD and ASHD subjects respectively. AD subjects exhibited significantly higher HDL and lower TG and TC/HDL ratios. MMSE did not correlate with any lipid parameters in AD. Discussion: Elevated TC, LDL and TG with normal HDL and TC/HDL ratio characterize the lipid profile in AD, which somewhat overlaps with but may be distinct from the cardiac risk profile. MMSE does not correlate with lipid parameters suggesting no interaction between cholesterol and cognition in AD. Show more

Keywords: cholesterol, lipid profile, Alzheimer's, atherosclerosis, lipids

DOI: 10.3233/JAD-2004-6602

Citation: Journal of Alzheimer's Disease, vol. 6, no. 6, pp. 585-589, 2004

Authors: Payão, Spencer Luiz Marques | de Labio, Roger Willian | Gatti, Luciano Lobo | Rigolin, Valdeci O.S. | Bertolucci, Paulo H.F. | de A.C. Smith, Marília

Article Type: Research Article

Abstract: Alzheimer disease (AD) is the most common neurodegenerative disorder in the elderly and is also considered a progeroid genetic syndrome. The etiology of AD is complex and the mechanisms underlying its pathophysiology remains to be clarified. Werner syndrome (WS) is a rare autosomal recessive disorder characterized as a segmental progeroid syndrome. The gene (WRN) was recently identified. Its product acts as a DNA helicase and exonuclease. This study investigates the association of AD with the WRN 1367 polymorphisms in samples of 67 DA patients, 56 elderly healthy and 66 young healthy controls. DNA was isolated from blood cells, amplified by …PCR and digested with PmaCI. We observed that the genotype distributions of WRN 1367 variants were within Hardy-Weinberg equilibrium in all subject samples. Furthermore, chi-square test comparison for genotype distributions and allele frequencies did not reveal any significant difference among the three groups of subjects (P>0.05). These results support the idea that these variants are not involved as a risk factor for developing AD. Show more

Keywords: Alzheimer's disease, Werner syndrome, WRN 1367 polymorphisms, risk factor, association study

DOI: 10.3233/JAD-2004-6603

Citation: Journal of Alzheimer's Disease, vol. 6, no. 6, pp. 591-594, 2004

Authors: Kashon, Michael L. | Ross, G. Webster | O'Callaghan, James P. | Miller, Diane B. | Petrovitch, Helen | Burchfiel, Cecil M. | Sharp, Dan S. | Markesbery, William R. | Davis, Daron G. | Hardman, John | Nelson, James | White, Lon R.

Article Type: Research Article

Abstract: We examined 204 decedents of the autopsy component of the Honolulu-Asia Aging Study, a longitudinal cohort study, who had been clinically assessed for dementia. A sensitive ELISA technique was used to quantify glial fibrillary acidic protein (GFAP), a marker for astrogliosis, in four specific cortical brain regions and assess associations between GFAP and 1) a measure of cognitive function, 2) several clinical dementia conditions, and 3) neuritic plaque (NP) and neurofibrillary tangle (NFT) formation. Cognitive function was inversely associated with GFAP in the occipital, parietal and temporal lobes, but not in the frontal lobe. This relationship remained significant when the …contribution of NP and NFT counts was removed. Further, compared to brain samples from non-demented individuals, significantly greater GFAP levels were found in samples from individuals diagnosed with Alzheimer's disease, mixed dementia, and vascular mediated dementia. Because elevated levels of GFAP reflect astroglial responses to even subtle forms of neural damage, our data indicate that increments in GFAP may provide independent, supporting evidence for the damage underlying dementia, even in the absence of other evidence of neuropathology such as the presence of NPs or NFTs. Our findings underscore the need to look beyond standard neuropathological measures putatively linked to specific neuropathological conditions in efforts to identify common cellular and molecular processes that contribute to dementia. Show more

Keywords: astrogliosis, GFAP, cognitive performance, dementia, Alzheimer's disease, neurotic plaque, neurofibrillary tangle

DOI: 10.3233/JAD-2004-6604

Citation: Journal of Alzheimer's Disease, vol. 6, no. 6, pp. 595-604, 2004

Authors: Ko, Li-Wen | Rush, Toni | Sahara, Naruhiko | Kersh, Jay S. | Easson, Colin | DeTure, Michael | Lin, Wen-Lang | Connor, Yamicia D. | Yen, Shu-Hui C.

Article Type: Research Article

Abstract: Intraneuronal deposition of microtubule-associated protein tau in filamentous aggregates constitutes a pathological hallmark of neurofibrillary degeneration that is characteristic of Alzheimer's disease (AD) and related disorders known collectively as tauopathies. Formation of such fibril inclusions, consisting of hyperphosphorylated tau in multiple isoforms, correlates with the severity of cognitive decline in AD. How neurofibrillary pathology evolves in tauopathy remains unclear at present, but availability of a cellular model with robust tau aggregation will permit experimental scrutiny of the mechanistic process leading to such neurodegeneration. Through the use of a serial transfection strategy in conjunction with a tau minigene construct, we succeeded …in generating conditional transfectants of human neuronal lineage that overproduce wild-type human brain tau in isoforms 4R0N, 3R1N and 4R1N via TetOff and ecdysone inducible expression mechanisms. Such transgenic overexpression of tau in multiple isoforms facilitated the assembly of filamentous tau aggregates that exhibit immunoreactivities, physicochemical properties, and ultrastructural attributes reminiscent of those found in human tauopathies. The conditional tau transfectants thus provide us with a useful tool to elucidate the molecular and cellular events leading to neurofibrillary degeneration and a convenient means to test hypothetical mechanisms implicated in the etiopathogenesis of AD and related tauopathies. Show more

Keywords: tau, conditional transfectant, tau fibrillogenesis, neurofibrillary degeneration, Alzheimer's disease, tauopathy

DOI: 10.3233/JAD-2004-6605

Citation: Journal of Alzheimer's Disease, vol. 6, no. 6, pp. 605-622, 2004

Authors: Kobayashi, Katsuji | Hayashi, Masahiro | Nakano, Hiroyuki | Shimazaki, Masao | Sugimori, Kaoru | Koshino, Yoshifumi

Article Type: Research Article

Abstract: The relationships between astrocytic apoptosis and both senile plaques and neurofibrillary tangles (NFT) in gray matter lesions were examined quantitatively in Alzheimer's disease (AD) brains. Seven cortical regions were examined in seven AD brains by terminal dUTP nick end-labeling and immunolabeling with antibodies to glial fibrillary acidic protein, phosphorylated tau protein (AT180), apoptosis-related proteins (caspase-3, bcl-2, and CD95), and beta amyloid protein. Senile plaques showed the lowest density in the cornu ammonis. The density of apoptotic astrocytes was significantly correlated with the density of uncored and cored senile plaques. Neuronal caspase-3 and CD95 expression levels were too low to allow …statistical assessment, but Bcl-2 was expressed strongly in the astrocytes and neurons with and without NFT. The correlation of the density of apoptotic astrocytes with apoptotic neurons and NFT was not statistically significant. The density of Bcl2-positive neurons correlated significantly with those of NFT and cored senile plaques, but Bcl2-positive astrocyte density showed no correlation with density of senile plaques or apoptotic astrocytes. These observations suggest that senile plaques may be a cause of astrocytic apoptosis in the gray matter, and that Bcl-2 protein is associated with NFT formation. Show more

Keywords: Alzheimer's disease, apoptosis, astrocytes, senile plaques, TUNEL

DOI: 10.3233/JAD-2004-6606

Citation: Journal of Alzheimer's Disease, vol. 6, no. 6, pp. 623-632, 2004

Authors: Boldyrev, Alexander | Koudinov, Alexey | Berezov, Temirboulat | Carpenter, David O.

Article Type: Research Article

Abstract: Acutely dissociated rat cerebellar granule cell neurons were incubated with amyloid-β (1–42) and studied by flow cytometry. Amyloid-β caused a dose-dependent loss of viability, as determined by intracellular accumulation of propidium iodide (PI),and that was not accompanied by significant elevation of intracellular calcium, measured by Fluo-3 or reactive oxygen species (ROS), measured by 2',7'-dihydro-dichlorfluorescein diacetate (DCF). Carnosine, a ROS scavenger and an inhibitor of non-enzymatic glycosylation, partially reduced cell death caused by amyloid-β. We conclude that amyloid-β causes a relatively acute loss of cell viability in cerebellar granule cell neurons, which does not result from either elevation of intracellular calcium …concentration or generation of ROS. Show more

Keywords: flow cytometry, reactive oxygen species, calcium, carnosine, cerebellum, granule cells, Alzheimer's disease

DOI: 10.3233/JAD-2004-6607

Citation: Journal of Alzheimer's Disease, vol. 6, no. 6, pp. 633-638, 2004

Authors: Miklossy, Judith | Khalili, Kamel | Gern, Lise | Ericson, Rebecca L. | Darekar, Pushpa | Bolle, Lorie | Hurlimann, Jean | Paster, Bruce J.

Article Type: Research Article

Abstract: The cause, or causes, of the vast majority of Alzheimer's disease cases are unknown. A number of contributing factors have been postulated, including infection. It has long been known that the spirochete Treponema pallidum, which is the infective agent for syphilis, can in its late stages cause dementia, chronic inflammation, cortical atrophy and amyloid deposition. Spirochetes of unidentified types and strains have previously been observed in the blood, CSF and brain of 14 AD patients tested and absent in 13 controls. In three of these AD cases spirochetes were grown in a medium selective for Borrelia burgdorferi. In the present …study, the phylogenetic analysis of these spirochetes was made. Positive identification of the agent as Borrelia burgdorferi sensu stricto was based on genetic and molecular analyses. Borrelia antigens and genes were co-localized with beta-amyloid deposits in these AD cases. The data indicate that Borrelia burgdorferi may persist in the brain and be associated with amyloid plaques in AD. They suggest that these spirochetes, perhaps in an analogous fashion to Treponema pallidum, may contribute to dementia, cortical atrophy and amyloid deposition. Further in vitro and in vivo studies may bring more insight into the potential role of spirochetes in AD. Show more

Keywords: Alzheimer's disease, amyloid, bacteria, Borrelia burgdorferi, chronic inflammation, lyme disease, spirochetes, syphilis

DOI: 10.3233/JAD-2004-6608

Citation: Journal of Alzheimer's Disease, vol. 6, no. 6, pp. 639-649, 2004

Authors: Summers, William K.

Article Type: Research Article

Abstract: Alzheimer's disease is infrequently a genetically driven disease. Rather it is the product of free radical injury inflicted over decades after an initial insult to the central nervous system (CNS). The brain is uniquely sensitive to oxidative injury. A variety of insults to the CNS are now associated with Alzheimer's disease. These include hypertension, diabetes, and head trauma. These then cause a cytokine cascade and microlocalized inflammation in the CNS, that in time results in clinical Alzheimer's disease. By the ninth decade of life over half of the population manifests Alzheimer's disease. Prevention or reversal of this pathophysiology will lie …in administration of effective antioxidant therapy with specific treatments when etiologies are known. Show more

DOI: 10.3233/JAD-2004-6609

Citation: Journal of Alzheimer's Disease, vol. 6, no. 6, pp. 651-657, 2004

Authors: Lovell, Mark A. | Xiong, Shuling | Xie, Chengsong | Davies, Peter | Markesbery, William R.

Article Type: Research Article

Abstract: Neurofibrillary tangles (NFT) containing paired helical filaments (PHF) composed of abnormally phosphorylated tau are one of the hallmark lesions of the Alzheimer's disease (AD) brain. Although phosphorylation of tau is thought to precede the formation of PHF, the kinases/phosphatases involved remain poorly understood. Here we report that treatment of primary rat cortical neuron cultures with cuprizone, a copper chelator, in combination with oxidative stress (Fe2+ /H2 O2 ), significantly increased aberrant tau phosphorylation identified by TG3 immunochemistry. To determine the potential contribution of glycogen synthase kinase-3 (GSK-3) to the phosphorylation of tau in this model, activity of GSK-3 was determined. …Cultures treated with cuprizone/Fe2+ /H2 O2 showed significantly increased GSK-3 activity compared with control cultures or cultures treated with cuprizone, or Fe2+ /H2 O2 alone. Concomitant treatment of cultures with lithium, a GSK-3 inhibitor, significantly decreased GSK-3 activity and reduced TG3 staining. Together these data suggest a culture model of hyperphosphorylated tau that implicates increased GSK-3 activity. Show more

Keywords: cortical neuron culture, hyperphosphorylated tau, glycogen synthase kinase-3, paired helical filaments

DOI: 10.3233/JAD-2004-6610

Citation: Journal of Alzheimer's Disease, vol. 6, no. 6, pp. 659-671, 2004