Journal of Alzheimer's Disease - Volume 6, issue 4

Article Type: Editorial

DOI: 10.3233/JAD-2004-6401

Citation: Journal of Alzheimer's Disease, vol. 6, no. 4, pp. 353-353, 2004

Authors: Sun, Miao-Kun | Alkon, Daniel L.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized by amyloid plaques, neurofibrillary tangles in the brain, cerebral hypoperfusion/hypometabolism, and amyloid angiopathy. The former two and cell loss occur late in the disease and are probably not the leading causes for the initial memory decline. Cerebral hypoperfusion is a pre-clinical event in AD and represents the most accurate indicator predicting the probable AD patients to develop AD in a future time. However, in young animals, cerebral hypoperfusion as those matching the reduction in AD has no significant effects on learning and memory. Here, we report that association of cerebral hypoperfusion (2-vessel occlusion) with cerebrovascular …amyloid (internal-carotid 0.5 mg β25-35 , an active fragment of Aβ) significantly impaired spatial learning and memory of young adult rats, while neither the same insult alone had significant impact. At the time when the spatial memory was impaired, in vitro recording revealed that the associated cerebral hypoperfusion and internal-carotid amyloid reduced the ability of the hippocampal CA1 network to generate cholinergic θ and the synaptic modification evoked by associative activation of cholinergic and GABAergic inputs. The results suggest that cerebral hypoperfusion and amyloid angiopathy may play an important role as associated events in initiating the early memory decline in AD. Show more

Keywords: Alzheimer's disease, cerebral hypoperfusion, cognition, hippocampus, 2-vessel occlusion, rats

DOI: 10.3233/JAD-2004-6402

Citation: Journal of Alzheimer's Disease, vol. 6, no. 4, pp. 355-366, 2004

Authors: Baum, Larry | Ng, Alex

Article Type: Research Article

Abstract: Curcumin is a polyphenolic diketone from turmeric. Because of its anti-oxidant and anti-inflammatory effects, it was tested in animal models of Alzheimer's disease, reducing levels of amyloid and oxidized proteins and preventing cognitive deficits. An alternative mechanism of these effects is metal chelation, which may reduce amyloid aggregation or oxidative neurotoxicity. Metals can induce Aβ aggregation and toxicity, and are concentrated in AD brain. Chelators desferrioxamine and clioquinol have exhibited anti-AD effects. Using spectrophotometry, we quantified curcumin affinity for copper, zinc, and iron ions. Zn2+ showed little binding, but each Cu2+ or Fe2+ ion appeared to bind …at least two curcumin molecules. The interaction of curcumin with copper reached half-maximum at ∼3–12 μM copper and exhibited positive cooperativity, with Kd1 ∼10–60 μM and Kd2 ∼1.3 μM (for binding of the first and second curcumin molecules, respectively). Curcumin-iron interaction reached half-maximum at ∼2.5–5 μM iron and exhibited negative cooperativity, with Kd1 ∼0.5–1.6 μM and Kd2 ∼50–100 μM. Curcumin and its metabolites can attain these levels in vivo, suggesting physiological relevance. Since curcumin more readily binds the redox-active metals iron and copper than redox-inactive zinc, curcumin might exert a net protective effect against Aβ toxicity or might suppress inflammatory damage by preventing metal induction of NF-κB. Show more

Keywords: curcumin, desferrioxamine, copper, iron, zinc, metal, Alzheimer's disease, AD, chelation, chelator

DOI: 10.3233/JAD-2004-6403

Citation: Journal of Alzheimer's Disease, vol. 6, no. 4, pp. 367-377, 2004

Authors: Challa, Venkat R. | Thore, Clara R. | Moody, Dixon M. | Anstrom, John A. | Brown, William R.

Article Type: Research Article

Abstract: String vessels are collagenous structures connected to capillaries. They have no endothelial cells or lumen. We assessed collagen IV-labeled string vessels in the white matter (WM) of subjects with Alzheimer's disease (AD) (n = 12) and non-AD controls (n = 11) using 100 μm celloidin sections. Ten standard fields were digitally captured and the number and length of normal vessels and string vessels were quantified by computerized image analysis. The WM of the AD-diagnosed individuals contained more strings per mm2 (3.95 ± 0.49) than comparable WM from controls (1.36 ± 0.39) (p = 0.0005) and had increased total string …vessel length in mm/mm2 (AD = 0.29 ± 0.04; control = 0.10 ± 0.03; p = 0.0015). There was a 25% increase (not statistically significant) in vessel density in mm/mm2 in AD subjects (AD = 11.88 ± 0.87; control = 9.53 ± 0.78; p = 0.06), presumably due to brain atrophy in the white matter. Although vessel length was slightly increased in AD subjects, they still had more than double the string length per total vessel length (AD = 2.88 ± 0.38) compared to controls (1.36 ± 0.27) (p = 0.0057). This increase in string vessels in the white matter of AD subjects suggests a decrease in vascular supply in this disease. Show more

Keywords: Alzheimer's disease, brain, arterioles, brain, vessels, brain, capillaries, celloidin, collagen, string vessels

DOI: 10.3233/JAD-2004-6404

Citation: Journal of Alzheimer's Disease, vol. 6, no. 4, pp. 379-383, 2004

Authors: Praticò, Domenico | Yao, Yuemang | Rokach, Joshua | Mayo, Martha | Silverberg, Gerald G. | McGuire, Dawn

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is associated with an increase in cerebrospinal fluid (CSF) levels of the isoprostane 8,12-iso-iPF2α -VI, a specific marker of in vivo lipid peroxidation. Poor cerebral clearance of end products of oxidative reactions via CSF circulation may contribute to and sustain ongoing stress. CSF drainage via a low-flow ventriculoperitoneal (VP) shunt may improve removal of these products, reducing oxidative stress. We quantified this biomarker in patients with AD undergoing to VP shunt placement at baseline and after one-year period. CSF sampling occurred at baseline and quarterly visits for one year. Levels of this isoprostane were determined simultaneously at …the end of the study by gas chromatography negative ion chemical ionization mass spectrometry. Over one-year, CSF 8,12-iso-iPF2α -VI levels consistently decreased versus baseline (51% of initial level), while CSF protein, glucose, cell count and IgG concentrations remained within normal limits. This finding supports the hypothesis that improving CSF drainage enhances extra-cellular clearance of end products of oxidative reactions and lowers brain lipid peroxidation. Show more

Keywords: Alzheimer's disease, oxidative stress, isoprostanes, cerebrospinal fluid

DOI: 10.3233/JAD-2004-6405

Citation: Journal of Alzheimer's Disease, vol. 6, no. 4, pp. 385-389, 2004

Authors: Tavares, Wagner Malagó | Sperança, Marcia Aparecida | de Labio, Roger Willian | Peres, Clovis A. | Okamoto, Ivan Hideyo | Bertolucci, Paulo Henrique Ferreira | Smith, Marília de A.C. | Payão, Spencer Luiz Marques

Article Type: Research Article

Abstract: Ribosomal genes are involved in cellular transcription, translation and gene expression modulation process. An association between 28S/18S rRNA ratio levels with apoptosis and aging has been reported. Moulder et al. [22] and Hashimoto et al. [8] showed an association between apolipoprotein E4 allele and neuronal cell apotosis through diverse mechanisms. The apoE 4 allele is considered a late-onset Alzheimer's disease (AD) risk factor associated with AD pathogenesis. We evaluated the association between apoE4 allele genotyping by PCR and rRNA 28S/18S ratio by slot blotting technique using peripheral blood samples of 18 Alzheimer's disease patients, 18 elderly controls and 18 young …controls. A rRNA ratio decrease was observed in AD individuals confirming our previous results but this association is independently of the ApoE4 allele genotype. Thus our results pointed that two different mechanisms are involved in the etiology of Alzheimer disease each one leading independently to cell death. Further studies could investigate these factors. Show more

Keywords: ageing, Alzheimer's disease, Ribosomal genes, apolipoprotein E, 28S/18SrRNA

DOI: 10.3233/JAD-2004-6406

Citation: Journal of Alzheimer's Disease, vol. 6, no. 4, pp. 391-395, 2004

Authors: Sliger, Melissa | Lander, Timothy | Murphy, Claire

Article Type: Research Article

Abstract: The present study investigated the effects of the apolipoprotein E (ApoE) ε4 allele, a risk factor for Alzheimer's disease (AD), on olfactory function in Down syndrome (DS). Brain areas critical to olfactory processing, particularly the entorhinal cortex, show the earliest neuropathological changes in AD. Functionally, odor identification has been shown to be impaired in AD and in persons with the ε4 allele. DS is also a risk factor for AD. Thus, we hypothesized greater impairment in ε4 positive DS participants. Olfactory function was assessed with the San Diego Odor Identification Test in 34 participants with DS and 34 normal controls. …Genomic DNA was prepared from blood samples to obtain ApoE status for the DS participants. Results indicate (1) that participants with DS had significant deficits in olfactory functioning; and (2) that among DS participants, those with an ε4 allele had poorer odor identification than those without an ε4 allele. The results support the hypothesis that individuals with DS who have an additional genetic risk factor for AD, the ApoE ε4 allele, exhibit greater deficits in odor identification. Areas of the brain involved in odor identification may be particularly affected in individuals with DS who carry the ε4 allele. Show more

Keywords: odor identification, smell, genetic risk, Alzheimer's disease, dementia

DOI: 10.3233/JAD-2004-6407

Citation: Journal of Alzheimer's Disease, vol. 6, no. 4, pp. 397-402, 2004

Authors: Joseph, James A. | Fisher, Derek R. | Carey, Amanda N.

Article Type: Research Article

Abstract: Evidence suggests that there is a selective sensitivity to oxidative stress (OSS) among muscarinic receptor (MAChR) subtypes with M1 , M2 and M4 showing > OSS than M3 or M5 subtypes in transfected COS-7 cells. This may be important in determining the regional specificity in neuronal aging and Alzheimer disease (AD). We assessed the effectiveness of blueberry (BB) and other high antioxidant (HA) fruit extracts (boysenberry, BY; cranberry, CB; black currant, BC; strawberry, SB; dried plums, DP; and grape, GR) on the toxic effects of Aβ 25–35 (100 μM, 24 hrs) and DA (1 mM, 4 …hrs) on calcium buffering (Recovery) following oxotremorine (750 μM) -induced depolarization in M1 AChR-transfected COS-7 cells, and on cell viability following DA (4 hrs) exposure. The extracts showed differential levels of Recovery protection in comparisons to the non-supplemented controls that was dependent upon whether DA or Aβ was used as the pretreatment. Interestingly, assessments of DA-induced decrements in viability revealed that all of the extracts had some protective effects. These findings suggest that the putative toxic effects of Aβ or DA might be reduced by HA fruit extracts. Show more

Keywords: oxidative stress, calcium flux, muscarinic receptors, amyloid beta, fruit extracts

DOI: 10.3233/JAD-2004-6408

Citation: Journal of Alzheimer's Disease, vol. 6, no. 4, pp. 403-411, 2004

Authors: Tang, Yu Ping | Haslam, Sandra Z. | Conrad, Susan E. | Sisk, Cheryl L.

Article Type: Research Article

Abstract: Estrogen replacement therapy in postmenopausal women is associated with a reduced risk of Alzheimer's Disease (AD). The multiple mechanisms by which estrogen protects against AD are still unknown. To conduct a broad screen for estrogen-regulated AD-related genes in the brain, we used cDNA array assays of brain mRNA samples from ovariectomized (ovx) adult female mice treated with either 17β-estradiol or vehicle at 1 or 5 weeks post-ovx. The gene encoding transthyretin (TTR), which has been reported to scavenge amyloid β peptides and reduce amyloid plaque formation, is increased by estradiol treatment at both 1 and 5 weeks post-ovx. Northern blot …analyses and RNase protection assays performed on whole brain samples obtained from estradiol- or vehicle-treated mice confirmed the cDNA array assays showing a significant increase in TTR mRNA with estradiol treatment. Qualitative in situ hybridization or immunocytochemistry performed on brain sections demonstrated that TTR mRNA is expressed only in choroid plexus and leptomeninges, and that both estrogen receptor proteins, α and β, are present in choroid plexus cells. These novel findings suggest that estrogen may reduce the risk of AD by acting on choroid plexus cells to increase TTR gene expression, leading to enhanced sequestration and reduced aggregation of amyloid β peptides. Show more

Keywords: estrogen, Alzheimer's disease, transthyretin

DOI: 10.3233/JAD-2004-6409

Citation: Journal of Alzheimer's Disease, vol. 6, no. 4, pp. 413-420, 2004

Authors: Lopez, E.M. | Bell, K.F.S. | Ribeiro-da-Silva, A. | Cuello, A.C.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) studies typically focus on the extracellular impact of the amyloid-beta (Aβ) protein, however recent findings also implicate intracellular Aβ (iAβ) accumulation in the disease's molecular neuropathology. In a double mutant transgenic rat model (AβPP and PS1 mutations, UKUR25), stably expressing intracellular human Aβ fragments in an environment devoid of both amyloid plaques and neurofibrillary tangles, we investigated the impact of iAβ burden on both the incidence and relative cross sectional areas of the Golgi apparatus, lysosomes and lipofuscin bodies. Pyramidal cells within the hippocampus and neocortex of both transgenic and non-transgenic age matched controls were compared. This …comparison revealed a significant increase in both the proportional area occupied by Golgi apparatus elements as well as in the mean individual cross sectional area of Golgi compartments in the hippocampus of transgenic rats as compared to controls. Elevated lysosome and lipofuscin elements in the hippocampi of transgenic rats were observed, as was an increase in the mean individual, cross sectional area of lipofuscin bodies in the cortex of transgenic rats as compared to controls. These findings support the hypothesis that intracellular Aβ accumulation not only has an impact on subcellular compartments but also potentially contributes to the neuronal cell pathology observed in AD. Show more

Keywords: Alzheimer's disease, amyloid β protein precursor, intracellular amyloid-beta protein, Golgi apparatus, lysosome, lipofuscin bodies

DOI: 10.3233/JAD-2004-6410

Citation: Journal of Alzheimer's Disease, vol. 6, no. 4, pp. 421-431, 2004