Journal of Alzheimer's Disease - Volume 17, issue 3

Authors: Hegde, Muralidhar L. | Bharathi, P. | Suram, Anitha | Venugopal, Chitra | Jagannathan, Ramya | Poddar, Pankaj | Srinivas, Pullabhatla | Sambamurti, Kumar | Rao, Kosagisharaf Jagannatha | Scancar, Janez | Messori, Luigi | Zecca, Luigi | Zatta, Paolo

Article Type: Review Article

Abstract: A close association between brain metal dishomeostasis and the onset and/or progression of Alzheimer's disease (AD) has been clearly established in a number of studies, although the underlying biochemical mechanisms remain obscure. This observation renders chelation therapy an attractive pharmacological option for the treatment of this disease. However, a number of requirements must be fulfilled in order to adapt chelation therapy to AD so that the term “metal targeted strategies” seems now more appropriate. Indeed, brain metal redistribution rather than brain metal scavenging and removal is the major goal of this type of intervention. The most recent developments in metal …targeted strategies for AD will be discussed using, as useful examples, clioquinol, curcumin, and epigallocatechin, and the future perspectives will also be outlined. Show more

Keywords: Alzheimer's disease, clioquinol, cuprizone, metal dishomeostasis, metal ions, nanomedicine, Parkinson's disease, polyphenols

DOI: 10.3233/JAD-2009-1068

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 457-468, 2009

Authors: Belinson, Haim | Michaelson, Daniel M.

Article Type: Review Article

Abstract: This review focuses on apolipoprotein E4 (apoE4), the most prevalent genetic risk factor of Alzheimer's disease, and on in vivo and in vitro model studies of the mechanisms underlying its pathological phenotype. The review will first center on in vivo studies with transgenic mice that express human apoE4 and other human apoE alleles, and on the extent to which this model mimics and reproduces the human apoE4 phenotypes. The second part of this review will address apoE4-related in vitro studies, with particular emphasis on the effects of the state of lipidation of apoE4 on its biochemical properties and on the …extent to which the in vitro results can be generalized and applied to the in vivo situation. The third part of this review will focus on a novel pharmacological in vivo system that was recently developed in our laboratory, which is based on activation of the amyloid cascade in apoE transgenic mice by prolonged inhibition of the Aβ-degrading enzyme neprilysin and on what this system and its high spatio-temporal resolution has taught us about the mechanisms underlying the pathological effects of apoE4 in vivo. Show more

Keywords: Amyloid-β, apolipoprotein E4, CA1 neurons, entorhinal cortex, lysosomes, neprilysin, neurodegeneration, septum

DOI: 10.3233/JAD-2009-1065

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 469-481, 2009

Authors: Chan, Amy | Rogers, Eugene | Shea, Thomas B.

Article Type: Short Communication

Abstract: Prior studies link dietary deficiency and genetic risk factors for Alzheimer's disease (AD). In the present report, mice expressing human apolipoprotein E4 (associated with increased risk of AD) and apolipoprotein E3 were subjected to a diet lacking folate and vitamin E, and containing iron as a pro-oxidant. Consistent with prior studies, E4 mice displayed more phospho-tau than E3 mice prior to dietary challenge. The deficient diet increased phospho-tau in E4 but not E3 mice, which was prevented by S-adenosyl methionine supplementation. Since neurofibrillary tangles are comprised of phospho-tau, investigation of the impact of dietary deficiency and S-adenosyl methionine supplementation on …neurofibrillary tangle formation are warranted. Show more

Keywords: Apolipoprotein E, folate, S-adenosyl methionine, tau, vitamin E

DOI: 10.3233/JAD-2009-1076

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 483-487, 2009

Authors: Wang, Rui | Wang, Suqing | Malter, James S. | Wang, Deng-Shun

Article Type: Research Article

Abstract: The cerebral accumulation of amyloid-β (Aβ) is a consistent feature of and likely contributor to the development of Alzheimer's disease (AD). In addition to dysregulated production, increasing experimental evidence suggests reduced catabolism plays an important role in Aβ accumulation. Although endothelin converting enzyme (ECE) and insulin degrading enzyme (IDE) degrade and thus contribute to regulating the steady-state levels of Aβ, how these enzymes are regulated remain poorly understood. In this study, we investigated the effects of 4-hydroxy-nonenal (HNE) and Aβ on the expression and activity of ECE-1 and IDE in human neuroblastoma SH-SY5Y cells. Treatment with HNE or Aβ upregulated …ECE-1 mRNA and protein, while IDE was unchanged. Although both ECE-1 and IDE were oxidized within 24 h of HNE or Aβ treatment, ECE-1 catalytic activity was elevated while IDE specific activity was unchanged. The results demonstrated for the first time that both ECE-1 and IDE are substrates of HNE modification induced by Aβ. In addition, the results suggest complex mechanisms underlying the regulation of their enzymatic activity. Show more

Keywords: Alzheimer's disease, amyloid-β, degradation, endothelin converting enzyme, 4-hydroxy-nonenal (HNE), insulin degrading enzyme, oxidative stress

DOI: 10.3233/JAD-2009-1066

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 489-501, 2009

Authors: Fonseca, Ana Catarina R.G. | Proença, Teresa | Resende, Rosa | Oliveira, Catarina R. | Pereira, Cláudia M.F.

Article Type: Research Article

Abstract: Statins, used as cholesterol-lowering drugs, were reported to reduce the progression of Alzheimer's disease (AD). However, the molecular mechanisms underlying these findings remain to be clarified and it is not well understood whether this beneficial effect is due to simply lowering cholesterol levels. This study was aimed to investigate the neuroprotective effect of simvastatin and lovastatin, lipophilic statins that can transverse the blood brain barrier, against the toxicity triggered by the AD-associated amyloid-β (Aβ) peptides and to analyze if such protection is cholesterol-independent. Using primary cultures of cortical neurons treated with Aβ1-40 peptide, we have demonstrated that pre-incubation with …statins prevents the rise in cytosolic Ca2+ concentration and the accumulation of reactive oxygen species induced by Aβ through mechanisms independent of cholesterol reduction. The neuroprotective actions of statins were rather attributable to their ability to reduce isoprenyl intermediates levels in the cholesterol biosynthetic pathway since their effect was reversed by geranyl pyrophosphate while cholesterol addition was ineffective. Consequently, statins were shown to rescue cortical neurons from Aβ1-40 -induced caspase-3-dependent apoptosis. Moreover, our results revealed that simvastatin, at neuroprotective concentrations against Aβ-induced toxicity, is not able to activate Akt or ERK2, two signaling kinases with neuroprotective roles against apoptosis. Show more

Keywords: Alzheimer's disease, amyloid-β, apoptosis, cortical neurons, isoprenoids, statins

DOI: 10.3233/JAD-2009-1067

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 503-517, 2009

Authors: de la Monte, Suzanne M. | Neusner, Alexander | Chu, Jennifer | Lawton, Margot

Article Type: Research Article

Abstract: Nitrosamines mediate their mutagenic effects by causing DNA damage, oxidative stress, lipid peroxidation, and pro-inflammatory cytokine activation, which lead to increased cellular degeneration and death. However, the very same pathophysiological processes comprise the “unbuilding” blocks of aging and insulin-resistance diseases including, neurodegeneration, diabetes mellitus (DM), and non-alcoholic steatohepatitis (NASH). Previous studies demonstrated that experimental exposure to streptozotocin, a nitrosamine-related compound, causes NASH, and diabetes mellitus Types 1, 2 and 3 (Alzheimer (AD)-type neurodegeneration). Herein, we review evidence that the upwardly spiraling trends in mortality rates due to DM, AD, and Parkinson's disease typify exposure rather than genetic-based disease models, and …parallel the progressive increases in human exposure to nitrates, nitrites, and nitrosamines via processed/preserved foods. We propose that such chronic exposures have critical roles in the pathogenesis of our insulin resistance disease pandemic. Potential solutions include: 1) eliminating the use of nitrites in food; 2) reducing nitrate levels in fertilizer and water used to irrigate crops; and 3) employing safe and effective measures to detoxify food and water prior to human consumption. Future research efforts should focus on refining our ability to detect and monitor human exposures to nitrosamines and assess early evidence of nitrosamine-mediated tissue injury and insulin resistance. Show more

Keywords: Alzheimer's disease, diabetes, environmental toxin, neurodegeneration, nitrosamine, obesity

DOI: 10.3233/JAD-2009-1070

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 519-529, 2009

Authors: Liang, Zhihou | Liu, Fei | Iqbal, Khalid | Grundke-Iqbal, Inge | Gong, Cheng-Xin

Article Type: Research Article

Abstract: Glutamate receptor-mediated excitotoxicity is thought to contribute to the development of Alzheimer's disease (AD), but the underlying mechanism is unknown. In this study, we investigated the dynamic changes of tau phosphorylation and tau-related protein kinases and protein phosphatase 2A (PP2A) in the mouse brain during excitotoxicity induced by intraperitoneal injection of 20 mg/kg kainic acid (KA). We found that KA-induced excitotoxicity led to transient dephosphorylation of tau (within 6 hr post-injection), followed by sustained hyperphosphorylation of tau at multiple sites that are hyperphosphorylated in AD brain. The initial dephosphorylation of tau may result from activation of PP2A, and the sustained …hyperphosphorylation may be due mainly to activation of cdk5 and down-regulation of PP2A during the later phase. Because abnormal hyperphosphorylation of tau plays a crucial role in neurodegeneration and in the formation of neurofibrillary tangles, our results suggest that glutamate receptor--mediated excitotoxicity might contribute to AD partially via promoting abnormal hyperphosphorylation of tau in AD brain. Show more

Keywords: Alzheimer's disease, glutamate receptors, kainic acid, phosphorylation, protein kinases, protein phosphatase-2A, tau

DOI: 10.3233/JAD-2009-1069

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 531-539, 2009

Authors: Jesse, Sarah | Steinacker, Petra | Cepek, Lukas | Arnim, Christine V. | Tumani, Hayrettin | Lehnert, Stefan | Kretzschmar, Hans A. | Baier, Michael | Otto, Markus

Article Type: Research Article

Abstract: Glial fibrillary acidic protein (GFAP) and protein S-100B are established indicators of astrogliosis in neuropathology. As GFAP and S-100B are expressed in different cell populations, variable cerebrospinal fluid (CSF) concentrations of these proteins might reflect disease-specific pathological profiles. Therefore we investigated CSF of patients with Alzheimer's disease (AD), patients with Creutzfeldt-Jakob disease (CJD), and non-demented control patients (CON). Measurement of GFAP and S-100B in CSF was performed by commercially available ELISA. Our results show that, in AD, there are significantly higher levels of GFAP concentrations, compared to CON (p = 0.001) and CJD patients (p = 0.009), whereas S-100B is …much higher in CJD, compared to AD (p = 0.001) and CON (p = 0.001). In conclusion, GFAP and S-100B represent astroglial markers and the different levels of these proteins in CSF of AD and CJD patients might point to a distinct pathophysiological involvement in these diseases. Apart from pathophysiological aspects, GFAP in particular might serve as an additional diagnostic tool for AD, due to the fact that this protein does not correlate to established markers like tau and amyloid-β such that analysis of GFAP may be useful for further differential diagnostic approaches in neurodegenerative diseases. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, Creutzfeldt-Jakob disease, glial fibrillary acidic protein, neurochemical diagnosis, S-100B

DOI: 10.3233/JAD-2009-1075

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 541-551, 2009

Authors: Jaeger, Laura B. | Dohgu, Shinya | Hwang, Mark C. | Farr, Susan A. | Murphy, M. Paul | Fleegal-DeMotta, Melissa A. | Lynch, Jessica L. | Robinson, Sandra M. | Niehoff, Michael L. | Johnson, Steven N. | Kumar, Vijaya B. | Banks, William A.

Article Type: Research Article

Abstract: Decreased clearance is the main reason amyloid-β protein (Aβ) is increased in the brains of patients with Alzheimer's disease (AD). The neurovascular hypothesis states that this decreased clearance is caused by impairment of low density lipoprotein receptor related protein-1 (LRP-1), the major brain-to-blood transporter of Aβ at the blood-brain barrier (BBB). As deletion of the LRP-1 gene is a lethal mutation, we tested the neurovascular hypothesis by developing a cocktail of phosphorothioate antisenses directed against LRP-1 mRNA. We found these antisenses in comparison to random antisense selectively decreased LRP-1 expression, reduced BBB clearance of Aβ42 , increased brain levels of …Aβ42 , and impaired learning ability and recognition memory in mice. These results support dysfunction of LRP-1 at the BBB as a mechanism by which brain levels of Aβ could increase and AD would be promoted. Show more

Keywords: Alzheimer's disease, antisense, blood-brain barrier, cognition, low density lipoprotein receptor related protein-1 (LRP-1), learning, memory, transporter

DOI: 10.3233/JAD-2009-1074

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 553-570, 2009

Authors: Teipel, Stefan J. | Meindl, Thomas | Wagner, Maximilian | Kohl, Thomas | Bürger, Katharina | Reiser, Maximilian F. | Herpertz, Sabine | Möller, Hans-Jürgen | Hampel, Harald

Article Type: Research Article

Abstract: The reduced risk of dementia in high-educated individuals has been suggested to reflect brain reserve capacity. In the present study, we determined the association between integrity of white matter microstructure and education separately in twenty-one patients with clinically probable Alzheimer's disease (AD) and 18 healthy elderly subjects. We used fractional anisotropy derived from high-resolution diffusion-tensor weighted imaging at 3 Tesla as an in vivo marker of white matter microstructure. Based on multivariate network analysis, more years of education were associated with reduced white matter integrity of medial temporal lobe areas and association fiber tracts when age, gender, and dementia severity …had been controlled for (p < 0.001). In controls, higher education was associated with greater white matter integrity in medial temporal lobe areas and association fiber tracts (p < 0.001). In multiple regression models, education was the main factor accounting for fiber tract integrity even when occupation was taken into account. Reduced fiber tract integrity with higher education at the same level of cognitive impairment in AD patients and higher fiber tract integrity with higher education in similar white matter areas in cognitively healthy controls agrees with the hypothesis that white matter microstructure may contribute to brain reserve capacity in humans. Show more

Keywords: Aging, Alzheimer's disease, brain reserve capacity, cortical connectivity, diffusion tensor imaging (DTI), education

DOI: 10.3233/JAD-2009-1077

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 571-583, 2009