Journal of Alzheimer's Disease - Volume 5, issue 6

Authors: Zambenedetti, Pamela | De Bellis, GianLuca | Biunno, Ida | Musicco, Massimo | Zatta, Paolo

Article Type: Research Article

Abstract: Several gene mutations are associated with an increased risk of Alzheimer's disease. Previous studies reported higher transferrin C2 allele frequencies in Alzheimer's disease compared with normal controls. However, potential interactions between transferrin C2 and APOE (ε4), have not been extensively investigated and have been the subject of controversial reports from several laboratories. We have carried out a case-control study on the association between Alzheimer's disease and transferrin C2 and APOE ε4 alleles. ε4 allele was associated with a four fold increase in the risk of disease, and transferrin C2 allele was significantly associated with Alzheimer's disease only in ε4 negative …subjects. These results suggest that apoE and transferrin may be part of a complex mechanism in the pathogenesis of Alzheimer's disease. Show more

Keywords: Alzheimer's disease, transferrin, apoE, iron

DOI: 10.3233/JAD-2003-5601

Citation: Journal of Alzheimer's Disease, vol. 5, no. 6, pp. 423-427, 2003

Authors: Reid, Richard T. | Sabbagh, Marwan N.

Article Type: Research Article

Abstract: Research on acetylcholinesterase inhibitors (ChEIs) indicates that long term exposure increases the level of nicotinic acetylcholine receptors (nAChRs) but the effects of donepezil on nAChRs are not well studied. Therefore, we investigated the effects of sub-chronic donepezil administration on nAChRs in rats and rat pheochromocytoma PC-12 cells. Male Sprague Dawley rats were administered donepezil (0.7 and 2.4 μmoles/kg), nicotine (2.5 μmoles/kg) or saline subcutaneously twice daily for 14 days, PC-12 cells were incubated with 10-6 to 10-4 M donepezil for 72 hours and nAChR levels were determined by receptor binding assay using the nAChR ligands [-3 H]-epibatidine (EPI) …for non-α7 nAChRs and [3 H]-methyllyconitine (MLA) for α7 nAChRs. Chronic donepezil administration at 1.4 μmoles/kg/day and 4.8 μmoles/ kg/day significantly increased [3 H]-epibatidine binding in the cortex to 126 ± 1.3% and 127 ± 3.2% of the saline control animals, respectively. [3 H]-MLA binding in the cortex increased to 114 ± 4.4% and 124 ± 2.8% of the control group for the high and low dose groups, respectively. Hippocampal [3 H]-EPI binding in the low dose and high dose groups significantly increased to 135 ± 3.6% and 125 ± 4.6% of the controls, respectively while there were no changes in the level of [3 H]-MLA binding. In striatal homogenates, neither [3 H]-EPI nor [3 H]-MLA binding were significantly effected at either dose of donepezil. In PC-12 cells, [3 H]-EPI binding was increased at the non-physiological 10-4 M concentration only. There was no effect of donepezil on [3 H]-MLA binding at any concentration examined. These results indicate that donepezil increases cortical α7 and non-α7 nAChRs, hippocampal non-α7 nAChRs but does not influence striatal nAChR levels. Furthermore, the lack of an effect on the α7-nAChRs in PC-12 cells suggests that the increase in cortical α7 nAChRs may be an indirect effect of increased acetylcholine levels in vivo. Show more

Keywords: donepezil, nicotinic receptor, Alzheimer's disease, PC-12 cells

DOI: 10.3233/JAD-2003-5602

Citation: Journal of Alzheimer's Disease, vol. 5, no. 6, pp. 429-436, 2003

Authors: Fattoretti, Patrizia | Bertoni-Freddari, Carlo | Balietti, Marta | Mocchegiani, Eugenio | Scancar, Janez | Zambenedetti, Pamela | Zatta, Paolo

Article Type: Research Article

Abstract: The effect of chronic aluminum intake has been investigated in the brain of aged male Wistar rats to assess the potential role of the accumulation of this metal ion on the development of neurodegenerative features observed in Alzheimer's disease. AlCl3 × 6 H2 O (2g/L) was administered to experimental animals for 6 months in the drinking water. The total content of Al (μg/g fresh tissue) was measured by inductively coupled plasma atomic emission spectrometry (ICP-AES), while the content of Cu, Zn and Mn was determined by flame AAS in the prosencephalon + mesencephalon, pons-medulla and cerebellum of control and …Al(III)-treated animals. The area occupied by mossy fibres in the CA3 field of the hippocampus was estimated by a computer-assisted morphometric method following Timm's preferential staining. In Al(III)-treated rats the concentration of Cu, Zn and Mn did not increase significantly (p < 0.5) in prosencephalon + mesencephalon, nor in pons-medulla (p < 0.5) except for Cu (p < 0.05) in pons-medulla. In the cerebellum the only significant increase was seen for Zn (p < 0.01) while no change was observed for Cu and Mn. The area occupied by the mossy fibres in the hippocampal CA3 field was significantly increased (+32%) in aged Al(III)-treated rats. Since Cu, Zn and Mn are essential components of the cytosolic and mitochondrial superoxide dismutases, it is possible that the increased content of these ions in aged Al(III)-treated rats represents an increased amount of genetic expression of these antioxidant enzymes. Considering that the positivity to Timm's reaction is based on the presence of free or loosely bound Zn+2 ions within synaptic terminals and that Zn2+ ions are reported to be accumulated by hippocampal neurons when tissue injury occurs, the increased area of the mossy fibres in CA3 field of Al(III)-treated rats could indicate increased hippocampal damage in these animals. Taken together, the present findings indicate that the aging CNS is particularly susceptible to Al(III) toxic effects which may increase the cell load of oxidative stress and may contribute, as an aggravating factor, to the development of neurodegenerative events as observed in Alzheimer's disease. Show more

DOI: 10.3233/JAD-2003-5603

Citation: Journal of Alzheimer's Disease, vol. 5, no. 6, pp. 437-444, 2003

Authors: Ferrer, Isidro | Hernández, Isabel | Puig, Berta | Jesús Rey, María | Ezquerra, Mario | Tolosa, Eduardo | Boada, Merce

Article Type: Research Article

Abstract: Neuropathological and biochemical findings are reported in a patient who had suffered from frontotemporal dementia associated with a P310L mutation in the tau gene and included in the H1 haplotype. tau accumulation, as revealed with phospho-specific anti-tau antibodies Thr181, Ser199, Ser202, Ser214, Ser262, Ser396, Ser422 and AT8 (Ser202 and Thr205), was found in neurons with pre-tangles, and astrocytes and oligodendrocytes through the brain. The most characteristic feature was tau immunoreactivity decorating the perinuclear region and small cytoplasmic aggregates designed as mini-Pick-like bodies, mainly in the dentate gyrus. Inclusions were not stained with anti-ubiquitin antibodies and did not recruit tubulins. …Tau accumulation in individual cells was associated with increased expression of kinases linked with tau phosphorylation, mainly active (phosphorylated) stress kinases SAPK/JNK and p38 (SAPK/JNK-P and p38-P). Phosphorylated GSK-3β at Ser9 (GSK-3β-P), that inactivates the kinase, was particularly abundant in mini-Pick-like bodies, thus suggesting alternative roles of GSK-3 probably involved in cell survival. Western blots of sarkosyl-insoluble fractions revealed a double band pattern of phospho-tau of 68/66 kDa and 64 kDa in the hippocampus and white matter in the P310L mutation. Sarkosyl-insoluble fractions of the hippocampus were enriched in p38-P and GSK-3β-P in Alzheimer's disease (AD) cases, processed in parallel for comparative purposes, but not in the P310L mutation. In addition, no bands of high molecular weight were found in P310L in contrast with AD in these fractions. These findings indicate that the major sites of tau phosphorylation, and the expression of kinases involved in tau phosphorylation are active in P310L mutation as in AD and other tauopathies. Yet the P310L mutation has particular phospho-tau inclusions that are not tag with ubiquitin and appear to be rather soluble when compared with AD. Show more

DOI: 10.3233/JAD-2003-5604

Citation: Journal of Alzheimer's Disease, vol. 5, no. 6, pp. 445-454, 2003

Authors: Lahousse, Stephanie A. | Stopa, Edward G. | Mulberg, Andrew E. | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: Background: The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes a ~150–165 kD glycoprotein that is mutated in individuals with cystic fibrosis. Previous studies demonstrated expression of the CFTR gene in the hypothalamus, suggesting a potential role for this molecule in the regulation of systemic metabolic functions. Individuals with cystic fibrosis often exhibit wasting and marked reductions in body fat content. Since the hypothalamus is a late target of neurodegeneration in Alzheimer's disease (AD), we postulated that patients with end-stage AD and bodily wasting would have reduced levels of CFTR expression in the hypothalamus. Methods: CFTR mRNA and …protein were examined in postmortem hypothalamic tissue from 11 AD and 7 aged controls using in situ hybridization and immunohistochemical staining. Standardized sections that included the supra-optic, paraventricular, anterior, and ventromedial nuclei, and the lateral hypothalamus were studied. Results: The density of CFTR+ neurons and the intensity of the CFTR hybridization signals were strikingly reduced in AD. Immunohistochemical staining studies demonstrated CFTR immunoreactivity most prominently distributed in small clusters of neurites (5 to 20 in number). Digital image quantification showed that the density of CFTR+ neurites was significantly reduced in AD relative to aged control samples (P=0.001). However, there was no evidence for selective involvement of particular hypothalamic nuclei. Conclusions: CFTR gene expression is down-regulated and its corresponding immunoreactivity reduced in AD relative to control hypothalamic tissue. Reduced CFTR expression in the hypothalamus may represent an important mechanism by which AD neurodegeneration contributes to body wasting in the late stages of disease. Show more

DOI: 10.3233/JAD-2003-5605

Citation: Journal of Alzheimer's Disease, vol. 5, no. 6, pp. 455-462, 2003

Authors: Ala, Thomas A. | Mattson, Michael D. | Frey II, William H.

Article Type: Research Article

Abstract: Although head imaging studies are frequently used in the work-up of dementia, published criteria for the clinical diagnosis of Alzheimer's disease (AD) do not require them. Since our brain bank contains cases in which physicians had specifically diagnosed AD without using a head imaging study, we thought it of interest to investigate the accuracy of their clinical diagnoses. We retrospectively reviewed 911 consecutive dementia cases for those clinically diagnosed as either AD or senile dementia (SD). Twenty-one were identified in which head imaging studies had not been used, each diagnosed as AD or SD by a different physician. In …only three had the physician reported a reason why a study was not done. In all 21 cases the primary neuropathological cause of the dementia was AD. Neuropathology in addition to AD was also noted, including cortical Lewy bodies in three, infarcts on gross examination in three, multiple microscopic infarcts in four, and multiple cerebral metastases in one. Acknowledging a number of study limitations, it is remarkable that the judgment of the physicians was correct regarding AD in all 21 cases. It is questionable if a head CT or MRI scan at time of diagnosis would have benefited any of the patients. Show more

Keywords: Alzheimer disease, CT scan, dementia, evaluation, neuroimaging

DOI: 10.3233/JAD-2003-5606

Citation: Journal of Alzheimer's Disease, vol. 5, no. 6, pp. 463-465, 2003

Authors: Woltjer, Randall L. | Maezawa, Izumi | Ou, Joyce J. | Montine, Kathleen S. | Montine, Thomas J.

Article Type: Research Article

Abstract: Carbonyl stress from products of lipid peroxidation, such as 4-hydroxynonenal (HNE), and products of sugars in diabetes mellitus, such as methylglyoxal (MG) and glyoxal (G), may contribute to neurodegeneration in Alzheimer's disease (AD). We tested the hypothesis that these carbonyls alter the proposed central pathogenic mechanism of AD, intracellular amyloid-β (Aβ)-mediated cytotoxicity, using a human neuroblastoma cell line that conditionally expresses carboxy-terminal fragments (CTFs) of the amyloid precursor protein. HNE was a potent cytotoxin, whereas G was mildly cytotoxic; cytotoxicity from each was independent of Aβ/CTF expression and not altered by α-tocopherol. In contrast, MG cytotoxicity was enhanced by the …induced expression of Aβ/CTFs and suppressed by α-tocopherol. α-tocopherol cytoprotection was accompanied by decreased Aβ/CTF aggregation. G also promoted Aβ/CTF aggregation but by mechanisms unaffected byα-tocopherol treatment. Our findings showed that Aβ/CTF aggregation and cytotoxicity may be profoundly altered by aldehydes associated with diabetes and that in the case of MG, this process is suppressed by α-tocopherol. Moreover, our results suggest that while intracellular aggregation of Aβ/CTFs may be necessary for the development of toxicity attributable to their expression in this model, the presence of high-molecular weight aggregated Aβ/CTFs does not invariably lead to cytotoxicity. Show more

Keywords: Alzheimer's, amyloid, methylglyoxal, glyoxal, HNE, aggregation, diabetes, tocopherol

DOI: 10.3233/JAD-2003-5607

Citation: Journal of Alzheimer's Disease, vol. 5, no. 6, pp. 467-476, 2003

Authors: Alisky, Joseph Martin

Article Type: Letter

DOI: 10.3233/JAD-2003-5608

Citation: Journal of Alzheimer's Disease, vol. 5, no. 6, pp. 477-478, 2003

Authors: Rafael, Hernando

Article Type: Letter

DOI: 10.3233/JAD-2003-5609

Citation: Journal of Alzheimer's Disease, vol. 5, no. 6, pp. 479-480, 2003

Authors: de la Monte, Suzanne M.

Article Type: Reply

DOI: 10.3233/JAD-2003-5610

Citation: Journal of Alzheimer's Disease, vol. 5, no. 6, pp. 481-482, 2003