Journal of Alzheimer's Disease - Volume 14, issue 2

Authors: Santos, Alexander Navarrete | Simm, Andreas | Holthoff, Vjera | Boehm, Gerald

Article Type: Short Communication

Abstract: A method for simultaneous quantification of amyloid-β1-40 , amyloid-β1-42 and amyloid-β oligomers in human plasma is described. The method consists of a combination of immunoprecipitation using specific antibodies against the different forms of amyloid-β, and immobilization of the immunocomplexes to magnetic beads. Addition of fluorescence-labelled antibodies which recognize the specific antibodies to the amyloid-β subsets allows the peptide/associates detection in the sample by flow cytometry. The clinical assay performance was tested using blood samples from Alzheimer disease's patients and control donors. A sensitivity of 70% and a specificity of 81% was achieved.

Keywords: Alzheimer's disease, amyloid-β, flow cytometry, human plasma, immunoprecipitation, magnetic beads

DOI: 10.3233/JAD-2008-14201

Citation: Journal of Alzheimer's Disease, vol. 14, no. 2, pp. 127-131, 2008

Authors: Granholm, Ann-Charlotte | Bimonte-Nelson, Heather A. | Moore, Alfred B. | Nelson, Matthew E. | Freeman, Linnea R. | Sambamurti, Kumar

Article Type: Research Article

Abstract: Diets rich in cholesterol and/or saturated fats have been shown to be detrimental to cognitive performance. Therefore, we fed a cholesterol (2%) and saturated fat (hydrogenated coconut oil, Sat Fat 10%) diet to 16-month old rats for 8 weeks to explore the effects on the working memory performance of middle-aged rats. Lipid profiles revealed elevated plasma triglycerides, total cholesterol, HDL, and LDL for the Sat-Fat group as compared to an iso-caloric control diet (12% soybean oil). Weight gain and food consumption were similar in both groups. Sat-Fat treated rats committed more working memory errors in the water radial arm maze, …especially at higher memory loads. Cholesterol, amyloid-β peptide of 40 (Aβ40) or 42 (Aβ42) residues, and nerve growth factor in cortical regions was unaffected, but hippocampal Map-2 staining was reduced in rats fed a Sat-Fat diet, indicating a loss of dendritic integrity. Map-2 reduction correlated with memory errors. Microglial activation, indicating inflammation and/or gliosis, was also observed in the hippocampus of Sat-Fat fed rats. These data suggest that saturated fat, hydrogenated fat and cholesterol can profoundly impair memory and hippocampal morphology. Show more

Keywords: Aging, cognitive impairment, dietary effects, memory, saturated fatty acids

DOI: 10.3233/JAD-2008-14202

Citation: Journal of Alzheimer's Disease, vol. 14, no. 2, pp. 133-145, 2008

Authors: Reale, Marcella | Iarlori, Carla | Feliciani, Claudio | Gambi, Domenico

Article Type: Research Article

Abstract: Cerebral inflammation as well as systemic immunological alterations has been reported in Alzheimer's disease (AD). We aimed to determine whether spontaneous and mitogen stimulated production of peripheral blood mononuclear cell (PBMC) cytokines, chemokines and chemokine receptors in clinically diagnosed patients with AD were unregulated. PBMC were purified from AD patients and from healthy controls. Supernatants were analyzed for cytokine levels by ELISA methods. mRNA expression was determined by RT-PCR. Expression of chemokine receptors CCR2 and CCR5 was determined by cytofluorimetric analysis. Both CCR5 and CCR2 expression were increased in AD patients respect to control subjects and the expression of CCR2 …and CCR5 was more frequent on CD4+ and less frequent on CD8+ cells. Levels of Th1-type cytokine IFNγ and chemokine RANTES were increased and levels of Th2-type cytokine IL-4 and chemokine MCP-1 were reduced in AD patients compared with those of control subjects. Acetylcholinesterase inhibitor pyridostigmine bromide (AChEI)-therapy reduced CCR2, CCR5, RANTES and IFNγ expression and production in AD patients. CCR5, CCL5/RANTES, CCL2/MCP-1 and IFNγ expression and production were increased in PBMC treated with amyloid-β1–42 . Addition of AChEI to PBMC suppresses CCL5/RANTES and IFNγ. The observed patterns of cyto-chemokine involvement strengthen the questions regarding the inflammatory theory in AD, and raise a pathophysiologic role for selective alteration of cyto-chemokine network. Show more

Keywords: Alzheimer's disease, CCL2/MCP-1, CCL5/RANTES, CCR2, CCR5, IFNγ, IL-4

DOI: 10.3233/JAD-2008-14203

Citation: Journal of Alzheimer's Disease, vol. 14, no. 2, pp. 147-159, 2008

Authors: Wang, Jun | Hara, Hideo | Makifuchi, Takao | Tabira, Takeshi

Article Type: Research Article

Abstract: Tissue amyloid plaque immuno-reactive (TAPIR) antibody was better related to the effect of immunotherapy in Alzheimer's disease (AD) than ELISA antibody. Here we used a hybridoma technique to develop a TAPIR-like anti-human amyloid-β (Aβ) mouse monoclonal antibody. The obtained monoclonal antibody, 3.4A10, was an IgG2b isotype and recognized N-terminal portion of Aβ1–42 without binding denatured or native amyloid-β protein precursor. It had higher affinity to Aβ1–42 than to Aβ1–40 by Biacore affinity analysis and stained preferably the peripheral part of senile plaques and recognized the plaque core less than 4G8. It inhibited the Aβ1–42 fibril formation …as well as degraded pre-aggregated Aβ1–42 peptide in a thioflavin T fluorescence spectrophotometry assay. The in vivo studies showed that 3.4A10 treatment decreased amyloid burden compared to the control group and significantly reduced Aβ42 levels rather than Aβ40 levels in brain lysates as well as the Aβ*56 oligomer (12mer) in TBS fraction of the brain lysates. 3.4A10 entered brain and decorated some plaques, which is surrounded by more Iba1-positive microglia. 3.4A10 therapy did not induce lymphocytic infiltration and obvious increase in microhemorrhage. We conclude that 3.4A10 is a TAPIR-like anti-human amyloid monoclonal antibody, and has a potential of therapeutic application for AD. Show more

Keywords: Alzheimer's disease, immunotherapy, TAPIR-like anti-amyloid antibody

DOI: 10.3233/JAD-2008-14204

Citation: Journal of Alzheimer's Disease, vol. 14, no. 2, pp. 161-173, 2008

Authors: Sambamurti, Kumar | Pappolla, Miguel A. | Rao, K.S. Jagannatha

Article Type: Article Commentary

DOI: 10.3233/JAD-2008-14205

Citation: Journal of Alzheimer's Disease, vol. 14, no. 2, pp. 175-177, 2008

Authors: Ampuero, Israel | Ros, Raquel | Royuela, Ana | Abraira, Victor | del Ser, Teodoro | García-Ribas, Guillermo | de Yébenes, Justo García

Article Type: Research Article

Abstract: We investigated the environmental and genetic factors for Alzheimer's disease (AD) in Spain and performed a door to door study of a cohort of more than 500 subjects, over 70 years old, from Leganés, a suburban area near Madrid. The cohort was followed for 6 years by neurologists and other health workers and was divided in three groups: normal controls, subjects with aging-associated cognitive decline (AACD) and probable AD or dementia of Alzheimer's type (DAT). Biological variables and polymorphisms of different genes, important in neurodegeneration or reported to be associated with AD, were investigated as putative risk modifiers. These polymorphisms …have also been analyzed in 94 brains, 39 from patients with pathologically confirmed AD and 55 controls. The statistical investigation included the evaluation of different individual risks and a multinomial logistic regression analysis to detect predictive factors. The risk of AACD and AD increased with age, feminine gender and history of stroke and decreased with education. The allele ApoE4 increased the risk of AD but not of AACD. When the impact of ApoE4 was added to the model, the effect of education and stroke disappeared as risk modifiers. Show more

Keywords: Alzheimer's disease, dementia, environmental risk factors, genetic polymorphisms, genetic risk factors

DOI: 10.3233/JAD-2008-14206

Citation: Journal of Alzheimer's Disease, vol. 14, no. 2, pp. 179-191, 2008

Authors: Emre, Murat | Mecocci, Patrizia | Stender, Karina

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder, constituting the most common cause of dementia. Memantine, an N-methyl-D-aspartate receptor antagonist indicated for the treatment of moderate to severe AD, has been shown to provide benefits in cognitive, functional, and behavioral domains in large, randomized clinical trials. The current analysis combined data from six previously published studies and assessed the effect of memantine on various cognitive functions in 1826 patients (867 on placebo and 959 on memantine) with moderate to severe AD (MMSE <20). The Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) and the Severe Impairment Battery (SIB) scores from all …six studies were pooled and combined into three clusters representing discrete cognitive domains: language, memory, and praxis. At baseline, there were no clinically significant differences between the memantine- and placebo-treated groups. After 24 weeks, responder analyses revealed that memantine treatment resulted in statistically significantly more patients improving on each of the three clusters, language, memory, and praxis, compared with placebo, and a lower percentage of patients treated with memantine showed any worsening on any of the three clusters compared with patients receiving placebo. It is concluded that treatment with memantine provides benefits in all three cognitive functions. Show more

Keywords: ADAS-cog, Alzheimer's disease, cognition, language, memantine, memory, praxis, SIB

DOI: 10.3233/JAD-2008-14207

Citation: Journal of Alzheimer's Disease, vol. 14, no. 2, pp. 193-199, 2008

Authors: Verdile, Giuseppe | Yeap, Bu B. | Clarnette, Roger M. | Dhaliwal, Satvinder | Burkhardt, Melanie S. | Chubb, S.A Paul | De Ruyck, Karl | Rodrigues, Mark | Mehta, Pankaj D. | Foster, Jonathan K. | Bruce, David G. | Martins, Ralph N.

Article Type: Research Article

Abstract: Dysregulation of the hypothalamic pituitary gonadal (HPG) axis during aging has been associated with increased risk of cognitive decline and developing dementia. Compared to controls, men with Alzheimer's disease (AD) have been shown to have lower serum testosterone levels and higher serum luteinizing hormone (LH) levels. As serum free testosterone concentration is negatively correlated with LH in older men, the independent contributions of these hormones to the pathogenesis of AD warrants further clarification. To explore this notion, we measured plasma amyloid-β (Aβ), serum testosterone, serum LH and other biochemical parameters in 40 cognitively normal elderly men. Multiple linear regression analysis …revealed that serum LH concentration is the only parameter that significantly correlates with plasma Aβ levels in these men (r=0.5, p=0.041). These results suggest that increased serum LH concentration, rather than lower serum free testosterone, is associated with the accumulation of Aβ in plasma. Larger, longitudinal human studies are needed to determine the significance of LH in the pathogenesis of AD. Show more

Keywords: Alzheimer's disease, amyloid-β, cognition, luteinizing hormone, testosterone

DOI: 10.3233/JAD-2008-14208

Citation: Journal of Alzheimer's Disease, vol. 14, no. 2, pp. 201-208, 2008

Authors: Man, Sui Cheung | Durairajan, Siva Sundara Kumar | Kum, Wan Fung | Lu, Jia Hong | Huang, Jian Dong | Cheng, Ching Fung | Chung, Vincent | Xu, Min | Li, Min

Article Type: Research Article

Abstract: A systematic review was conducted to assess the efficacy and safety of herbal medications (HM), as either monotherapy or adjunct to orthodox medications (cholinesterase inhibitors and nootropic agents, OM) for Alzheimer's disease (AD). Sixteen studies testing different HM were included. Out of the 15 HM monotherapy studies, 13 reported HM to be significantly better than OM or placebo; one reported similar efficacy between HM and OM. Only the HM adjuvant study reported significant efficacy. No major adverse events for HM were reported and HMs were found to reduce the adverse effects arising from OM. Imbalance in ethnicity among participants was …observed; gender distribution was unclear. Heterogeneity in diagnostic criteria, interventions and outcome measures hindered comprehensive data analysis. Studies comparing HM with OM suggest that HM can be a safe, effective treatment for AD, either alone or in conjunction with OM. Methodological flaws in the design of the studies, however, limited the extent to which the results could be interpreted. Among various HMs, the safety and tolerability of EGb761 was best established. Further multi-center trials with large sample size, high methodological qualities and standardized HM ingredients are necessary for clinical recommendations on the use of HM in treating AD. Show more

Keywords: Alzheimer's disease, clinical trial, herbal medicine, systematic review

DOI: 10.3233/JAD-2008-14209

Citation: Journal of Alzheimer's Disease, vol. 14, no. 2, pp. 209-223, 2008

Authors: Wadsworth, Teri L. | Bishop, James A. | Pappu, Anuradha S. | Woltjer, Randall L. | Quinn, Joseph F.

Article Type: Research Article

Abstract: Increasing evidence suggests that Alzheimer's disease (AD) is associated with oxidative damage that is caused in part by mitochondrial dysfunction. Here we investigated the feasibility of modifying Alzheimer pathology with the mitochondrial antioxidant coenzyme Q (CoQ). Exogenous CoQ protected MC65 neuroblastoma cells from amyloid-β protein precursor C-terminal fragment (APP CTF)-induced neurotoxicity in a concentration dependent manner, with concentrations of 6.25 μM and higher providing near complete protection. Dietary supplementation with CoQ at a dose of 10 g/kg diet to C65/Bl6 mice for one month significantly suppressed brain protein carbonyl levels, which are markers of oxidative damage. Treatment for one month …with 2 g lovastatin/kg diet, which interferes with CoQ synthesis, resulted in a significant lowering of brain CoQ10 levels. Mitochondrial energetics (brain ATP levels and mitochondrial membrane potential) were unaffected by either CoQ or lovastatin treatment. Our results suggest that oral CoQ may be a viable antioxidant strategy for neurodegenerative disease. Our data supports a trial of CoQ in an animal model of AD in order to determine whether a clinical trial is warranted. Show more

Keywords: Alzheimer's disease, coenzyme Q, lovastatin, MC65, Tg2576

DOI: 10.3233/JAD-2008-14210

Citation: Journal of Alzheimer's Disease, vol. 14, no. 2, pp. 225-234, 2008

Authors: Collingwood, Joanna F. | Chong, Ryan K. K. | Kasama, Takeshi | Cervera-Gontard, Lionel | Dunin-Borkowski, Rafal E. | Perry, George | Pósfai, Mihály | Siedlak, Sandra L. | Simpson, Edward T. | Smith, Mark A. | Dobson, Jon

Article Type: Research Article

Abstract: Although it has been known for over 50 years that abnormal concentrations of iron are associated with virtually all neurodegenerative diseases, including Alzheimer's disease, its origin, nature and role have remained a mystery. Here, we use high-resolution transmission electron microscopy (HR-TEM), energy dispersive X-ray (EDX) spectroscopy and electron energy-loss spectroscopy (EELS), electron tomography, and electron diffraction to image and characterize iron-rich plaque core material – a hallmark of Alzheimer's disease pathology – in three dimensions. In these cores, we unequivocally identify biogenic magnetite and/or maghemite as the dominant iron compound. Our results provide an indication that abnormal iron biomineralization processes …are likely occurring within the plaque or the surrounding diseased tissue and may play a role in aberrant peptide aggregation. The size distribution of the magnetite cores implies formation from a ferritin precursor, implicating a malfunction of the primary iron storage protein in the brain. Show more

Keywords: Alzheimer's disease, amyloid, electron microscopy, ferritin, imaging, iron, magnetite, senile plaque core, tomography

DOI: 10.3233/JAD-2008-14211

Citation: Journal of Alzheimer's Disease, vol. 14, no. 2, pp. 235-245, 2008

Authors: Lieberman, Andrew P. | Robins, Diane M.

Article Type: Review Article

Abstract: The androgen receptor (AR) is a ligand-activated transcription factor that is central to androgen-dependent development and diseases. Activity of the receptor is influenced by the length of a CAG/glutamine tract in its N-terminal transactivating domain. Expansions of this tract cause Kennedy disease, a protein aggregation degenerative disorder of motor neurons that occurs only in men, and shorter length tracts have been linked to increased risk of prostate cancer. Here we review recent data from mouse models in which gene targeting was used to humanize the mouse Ar gene and introduce CAG/glutamine tracts of varying lengths. Insertion of an expanded tract …encoded by 113 CAG repeats modeled Kennedy disease and revealed an important myopathic contribution to the disease phenotype. Variations in CAG tract length within the range of normal human alleles influenced the onset and progression of prostate cancer when targeted Ar mice were crossed to a transgenic prostate cancer model. This series of mice with different Ar alleles has provided insights into the mechanisms by which variations in the CAG/glutamine tract length influence the occurrence of human disease. Show more

Keywords: Androgen receptor, CAG/polyglutamine, Kennedy disease, mouse models, prostate cancer

DOI: 10.3233/JAD-2008-14212

Citation: Journal of Alzheimer's Disease, vol. 14, no. 2, pp. 247-255, 2008

Article Type: Announcement

DOI: 10.3233/JAD-2008-14213

Citation: Journal of Alzheimer's Disease, vol. 14, no. 2, pp. 257-258, 2008