Journal of Alzheimer's Disease - Volume 5, issue 1

Authors: Hone, E. | Martins, I.J. | Fonte, J. | Martins, R.N.

Article Type: Research Article

Abstract: The relationship between amyloid-β protein (Aβ) metabolism and Alzheimer's disease is currently poorly understood. While it is well known that the generation of Aβ results from enzymatic cleavage of its parent molecule, the amyloid β protein precursor (AβPP), there is little information available regarding its in vivo clearance. The E4 isoform of apolipoprotein E (apoE) has been associated with poor clearance of Aβ under in vitro conditions. This is thought to be due to its poor ability to bind Aβ compared with the other common isoforms, apoE2 and apoE3. Although cell culture studies support the notion that Aβ clearance …depends upon apoE isoform, validation of these findings requires Aβ clearance studies in vivo. In this study, we examined the clearance of Aβ in vivo from the periphery in mice that expressed apoE (C57BL/6J) or lacked apoE (APOE knockout). We measured the clearance of peripherally injected Aβ over time and additionally, the quantities sequestered by peripheral organs. Western blot analysis of the murine plasma indicated that the half-life of Aβ in the periphery was approximately 15 minutes. The livers of the C57BL/6J mice were found to have sequestered approximately 40% of the total injected Aβ at 90 minutes post-injection, whilst their kidneys contained 5% of the total injected Aβ. In contrast, the livers and kidneys of the APOE knockout animals were found to contain no detectable Aβ. These findings indicate that Aβ is rapidly removed from the plasma by murine peripheral tissues and the rate of its clearance is affected by apoE. Show more

Keywords: Amyloid-β protein, mouse, clearance, Alzheimer's disease, periphery, apolipoprotein E

DOI: 10.3233/JAD-2003-5101

Citation: Journal of Alzheimer's Disease, vol. 5, no. 1, pp. 1-8, 2003

Authors: Shea, Thomas B. | Rogers, Eugene | Ashline, David | Ortiz, Daniela | Duarte, Nancy | Wilson, Thomas O. | Nicolosi, Robert J. | Sheu, Min-Shyan

Article Type: Research Article

Abstract: Compensatory upregulation in endogenous antioxidants has been shown to accompany certain genetic and dietary deficiencies that promote oxidative stress, including that related to Alzheimer's disease. We compared antioxidant levels in brain tissue of normal and transgenic mice lacking apolipoprotein E following dietary deprivation of vitamin E or folate. As described previously, ApoE-deficient mice displayed increased levels of the endogenous antioxidant glutathione as compared to normal mice, and increased these levels further following folate deprivation. By contrast, glutathione was depleted following vitamin E deprivation in brain tissue of normal and ApoE-deficient mice. TBAR analyses confirmed increased oxidative damage following vitamin E …deprivation. However, combined deprivation of folate and vitamin E resulted in levels of glutathione intermediate between those observed following deprivation of either agent, indicating that the lack of compensatory increase in glutathione following vitamin E deprivation was not due to overt neurotoxicity. Similar results were observed for total antioxidant levels in brain tissue. The differential response to vitamin E and folate deprivation is consistent with the possibility that specific differences in oxidative damage may result from deficiencies in either of these agents. The lack of a compensatory response to vitamin E deprivation highlights the importance of dietary vitamin E in prevention of chronic neurodegeneration. Show more

DOI: 10.3233/JAD-2003-5102

Citation: Journal of Alzheimer's Disease, vol. 5, no. 1, pp. 9-14, 2003

Authors: Mishra, Ravi Shankar | Bose, Sharmila | Gu, Yaping | Li, Ruliang | Singh, Neena

Article Type: Research Article

Abstract: Although familial prion disorders are a direct consequence of mutations in the prion protein gene, the underlying mechanisms leading to neurodegeneration remain unclear. Potential pathogenic mechanisms include abnormal cellular metabolism of the mutant prion protein (PrPM ), or destabilization of PrPM structure inducing a change in its conformation to the pathogenic PrP-scrapie (PrPSc ) form. To further clarify these mechanisms, we investigated the biogenesis of mutant PrP V203I and E211Q associated with Creutzfeldt-Jakob disease, and PrP Q212P associated with Gerstmann-Straussler-Scheinker syndrome in neuroblastoma cells. We report that all three PrPM forms accumulate similarly in the cytosol in response …to proteasomal inhibition, and finally assemble as classical aggresomes. Since the three PrPM forms tested in this report are distinct, we propose that sequestration of misfolded PrPM into aggresomes is likely a general response of the cellular quality control that is not specific to a particular mutation in PrP. Moreover, since PrP has the remarkable ability to refold into PrPSc that can subsequently replicate, PrPM sequestered in aggresomes may cause neurotoxicity by both direct and indirect pathways; directly through PrPSc aggregates, and indirectly by depleting normal PrP, through induction of a cellular stress response, or by other undefined pathways. On the other hand, sequestered PrPM may be relatively inert, and cellular toxicity may be mediated by early intermediates in aggresome formation. Taken together, these observations demonstrate the role of proteasomes in the pathogenesis of familial prion disorders, and argue for further explanation of its mechanistic details. Show more

Keywords: CJD, GSS, familial prion disorders, proteasomes, aggresomes

DOI: 10.3233/JAD-2003-5103

Citation: Journal of Alzheimer's Disease, vol. 5, no. 1, pp. 15-23, 2003

Authors: Gasic-Milenkovic, Jovana | Loske, Claudia | Münch, Gerald

Article Type: Research Article

Abstract: Advanced glycation endproducts (AGEs), sugar-derived protein modifications and lipid peroxidation products are prominent features of Alzheimer's disease. AGEs accumulate on β-amyloid plaques during the course of the disease and can exert chronic oxidative stress via receptor-mediated mechanisms. Lipid peroxidation products such as hydroxynonenal, further markers of oxidative stress, are also increased in Alzheimer's diesease. In this study we present evidence for a direct biochemical link between AGEs and lipid peroxidation. Our results show that AGEs induce lipid peroxidation in a neuronal cell line in a dose-dependant manner, and that blocking the specific AGE-receptor RAGE, as well as using different antioxidants …(α-lipoic acid, N-acetylcysteine, 17 β-estradiol or aminoguanidine) can reduce the AGE-mediated formation of lipid peroxidation products. Thus, both RAGE antagonists and scavengers of oxygen free radicals could be useful in protecting brain tissue from lipid peroxidation and its pathophysilogical consequences that occur in Alzheimer's disease. Show more

Keywords: glycation, Alzheimer's disease, lipid peroxidation, antioxidants, RAGE, α-lipoic acid, hydroxynonenal

DOI: 10.3233/JAD-2003-5104

Citation: Journal of Alzheimer's Disease, vol. 5, no. 1, pp. 25-30, 2003

Authors: Becaria, Angelica | Bondy, Stephen C. | Campbell, Arezoo

Article Type: Research Article

Abstract: The etiology of Alzheimer's Disease (AD) is multifactorial. It has been suggested that transition metals such as copper (Cu) and iron (Fe) as well as aluminum (Al) may be involved in the pathogenesis of the disorder. While Cu and Fe are redox-active, Al only exists in the trivalent form and is redox-inert. We previously demonstrated that Al exposure causes an increase in inflammatory parameters in human glioblastoma T98G cells. In the present study we further demonstrate that co-exposure with Cu exacerbates the oxidative but not inflammatory effects of Al in this cell line. While Cu-induced reactive oxygen species (ROS) production …was greatly enhanced in the presence of Al, TNF-α secretion induced by either metal was not further potentiated by simultaneous exposure to Al and Cu. Furthermore, exposure to both metals reduced the individual Al and Cu-induced activation of the immune-related transcription factor NF-κB. Therefore, while synergistic interaction between the two metals increases oxidative events, this does not lead to potentiation of Al-induced inflammation. Thus the ability of aluminum to promote inflammatory processes does not depend on an increase ROS production induced by interaction with transition metals. Show more

Keywords: neuroinflammation, cytokines, NF-κB, oxidative stress

DOI: 10.3233/JAD-2003-5105

Citation: Journal of Alzheimer's Disease, vol. 5, no. 1, pp. 31-38, 2003

Authors: Ikonomovic, Milos D. | Mufson, Elliott J. | Wuu, Joanne | Cochran, Elizabeth J. | Bennett, David A. | DeKosky, Steven T.

Article Type: Research Article

Abstract: Several recent studies indicate that activity of cholinergic enzymes in the cortex of people with mild cognitive impairment (MCI) and early Alzheimer's disease (AD) are preserved. We correlated levels of hippocampal choline acetyltransferase (ChAT) activity with the extent of AD lesions in subjects from the Religious Order Study, including cases with no cognitive impairment (NCI), MCI, and with mild to moderate AD. Hippocampal ChAT activity levels were also determined in a group of end-stage AD patients who were enrolled in the University of Pittsburgh Alzheimer's Disease Research Center. MCI subjects were characterized with increased hippocampal ChAT activity. This elevation was …no longer present in mild AD cases, which were not different from NCI subjects. Severe AD cases showed markedly depleted hippocampal ChAT levels. In NCI, MCI, and mild-moderate AD, there was a positive correlation between hippocampal ChAT activity levels and progression of neuritic plaque pathology in entorhinal cortex and hippocampus. A significant elevation of hippocampal ChAT in the MCI group was found selectively in the limbic (i.e., entorhinal-hippocampal, III/IV) Braak stages. We hypothesize that cholinergic changes in the hippocampus of MCI subjects reflect a compensatory response to the progressive denervation of the hippocampus by lost entorhinal cortex input. Moreover, the present findings suggest that the short-term memory loss observed in MCI is not caused by cholinergic deficits; it more likely relates to disrupted entorhinal-hippocampal connectivity. Show more

DOI: 10.3233/JAD-2003-5106

Citation: Journal of Alzheimer's Disease, vol. 5, no. 1, pp. 39-48, 2003

Authors: Mićić, Dejan V. | Petronijević, Natasa D. | Vučetić, Svetlana S.

Article Type: Research Article

Abstract: In this study, the activity of total superoxide dismutase was investigated in brains of adult Mongolian gerbils (Meriones unguiculatus) treated with aluminum. AlCl3 ×6H2 O, was given “per os” in the amount of 3.7 g/kg body weight. Animals were killed 24, 48, 72 and 96 hours after the treatment and SOD activity was measured in crude mitochondrial fractions of cortex, thalamus and hippocampus. The SOD activity was significantly elevated in all investigated brain regions 24 hours after aluminum administration. The most prominent increases (up to 200% of values in control animals) were detected in thalamus and hippocampus, whereas the activity …was 165% of control value in the cortex. The SOD activity returned to control values in all regions investigated forty-eight hours after poisoning. A slight secondary increases in SOD activity were observed at 72 hours, reaching 171%, 148%, and 166% of control values in the thalamus, hippocampus and cortex, respectively, 96 hours after AlCl3 ×6H2 O administration. We conclude that Al administration causes a biphasic stimulation of SOD activity in various brain regions over 96 hours, providing evidence that oxidative stress is involved in aluminum toxicity to the brain. Show more

Keywords: Alzheimer's disease, SOD, aluminum, Mongolian gerbil, oxidative stress

DOI: 10.3233/JAD-2003-5107

Citation: Journal of Alzheimer's Disease, vol. 5, no. 1, pp. 49-56, 2003

Authors: Sabbagh, Marwan N. | Silverberg, Nina | Majeed, Bashar | Samant, Shefali | Sparks, D. Larry | Seward, James | Connor, Donald J.

Article Type: Research Article

Abstract: Studies estimate prolonged stays in acute and sub-acute facilities for patients with dementia. Actuarial projections suggest prolonged stays in long term care facilities for patients with dementia. To test these predictions, we assessed whether patients with dementia stay in skilled nursing facilities (SNF) longer than patients without dementia. We obtained medical records of 5,373 residents discharged from a SNF between 1996 and 2001. Residents were identified as having dementia by ICD-9 codes. Age, sex and length of stay (LOS), measured in days from admission to discharge or death, were gathered. Mean LOS for patients with dementia (92.7 ± 313.0, n …= 758) was significantly longer than non-demented patients (29.7 ± 136.8, n = 4615, p < 0.001). In a subset of individuals who stayed until death, the mean LOS for patients with dementia (202.9 ± 528.6, n = 195) also was significantly longer than for non-demented patients (91.8 ± 300.5, n = 610, p < 0.001). LOS was increased for demented patients even within age groups. Thus, patients with dementia stay in SNFs significantly longer from entry until discharge or death. It is likely that demented patients enter for non-physical, cognitive related reasons. These results may help families and institutions plan for long-term care. Show more

Keywords: skilled nursing facility, length of stay, dementia

DOI: 10.3233/JAD-2003-5108

Citation: Journal of Alzheimer's Disease, vol. 5, no. 1, pp. 57-63, 2003