Volume 7, Number 2, April 2005

Pages 99-100
Hernando Rafael
Letter to the Editor: Secondary Alzheimer started by cryptococcal meningitis

Page 101
Thomas Ala
Response to the Letter to the Editor

Pages 103-117
P. Hemachandra Reddy, Geethalakshmi Mani, Byung S. Park, Joline Jacques, Geoffrey Murdoch, William Whetsell Jr., Jeffrey Kaye, Maria Manczak
Differential loss of synaptic proteins in Alzheimer’s disease: Implications for synaptic dysfunction
Abstract: The objective of our research was to determine synaptic protein levels in brain specimens from AD subjects and age-matched control subjects. Further, to determine whether presynaptic or postsynaptic compartments of neurons are preferentially affected in AD patients, we studied 3 presynaptic vesicle proteins (synaptotagmin, synaptophysin, and Rab 3A), 2 synaptic membrane proteins (Gap 43 and synaptobrevin), and 2 postsynaptic proteins (neurogranin and synaptopodin) in specimens from AD and age-matched control brains. Two brain regions – the frontal and parietal cortices – were assessed for protein levels by immunoblotting analysis. We found a loss of both presynaptic vesicle proteins and postsynaptic proteins in all brain specimens from AD patients compared to those from age-matched control subjects. Further, we found that the loss of synaptic proteins was more severe in the frontal cortex brain specimens than in the parietal cortex brain specimens from the AD subjects compared to those from the control subjects, suggesting that the frontal brain may be critical for synaptic function in AD. Using immunohistochemistry techniques, we also determined the distribution pattern of all synaptic proteins in both the frontal and parietal cortices brain specimens from control subjects. Of the 7 synaptic proteins studied, the presynaptic proteins synaptophysin and rab 3A and the postsynaptic protein synaptopodin were the most down-regulated. Our study suggests that postsynaptic proteins and presynaptic proteins are important for synaptic function and may be related to cognitive impairments in AD.

Pages 119-124
Jianping Jia, Erhe Xu, Yankun Shao, Jianmin Jia, Yongxin Sun, Dan Li (Communicated by Yuan Luo)
One novel presenilin-1 gene mutation in a Chinese pedigree of familial Alzheimer’s disease
Abstract: This study is to explore whether there is presenilin 1 (PS 1) gene mutation in Chinese familial Alzheimer’s disease (FAD). There has been no such systemic research before in China. Using polymerase chain reaction, single strand conformation polymorphism (PCR-SSCP), followed by denaturing high performance liquid chromatograph (DHPLC) and DNA sequencing, we analyzed a Chinese family with early onset AD. The patients in this family showed a novel missense mutation in exon 4 of the PS1 gene (G to T change in codon 97), altering valine to leucine acid substitution. Because the change occurred in conserved domains of this gene, and is not present in normal controls, this novel mutation is likely to be causative of Chinese FAD.

Pages 125-133
Jing Zhang, Dave R. Goodlett, Joseph F. Quinn, Elaine Peskind, Jeffrey A. Kaye, Yong Zhou, Catherine Pan, Eugene Yi, Jimmy Eng, Qin Wang, Ruedi H. Aebersold, Thomas J. Montine
Quantitative proteomics of cerebrospinal fluid from patients with Alzheimer disease
Abstract: Biomarkers to assist in the diagnosis and medical management of Alzheimer disease (AD) are a pressing need. We have employed a proteomic approach, microcapillary liquid chromatography mass spectrometry of proteins labeled with isotope-coded affinity tags (ICAT), to quantify relative changes in the proteome of human cerebrospinal fluid (CSF) obtained from the lumbar cistern. Using CSF from well-characterized AD patients and age-matched controls at 2 different institutions, we quantified protein concentration ratios of 42% of the 390 CSF proteins that we have identified and found differences > 20% in over half of them. We confirmed our findings by western blot and validated this approach by quantifying relative levels of amyloid precursor protein and cathepsin B in 17 AD patients and 16 control individuals. Quantitative proteomics of CSF from AD patients compared to age-matched controls, as well as from other neurodegenerative diseases, will allow us to generate a roster of proteins that may serve as specific biomarker panels for AD and other geriatric dementias.

Pages 135-138
Flaubert Tchantchou, Michael Graves, Eugene Rogers, Daniela Ortiz, Thomas B. Shea
N-acteyl cysteine alleviates oxidative damage to central nervous system of ApoE-deficient mice following folate and vitamin E-deficiency
Abstract: Oxidative stress is an early neurodegenerative insult in Alzheimer’s disease (AD). Antioxidant mechanisms, including elements of the glutathione (GSH) pathway, undergo at least a transient compensatory increase that is apparently insufficient due to continued oxidative damage during disease progression. Mice deficient in apolipoprotein E, which provide a model for some aspects of AD, undergo increased oxidative damage to brain tissue and cognitive decline when maintained on a folate-free diet, despite a compensatory increase in glutathione synthase transcription and activity as well as increased levels of GSH. Dietary supplementation with N-acetyl cysteine (1g/kg diet), a cell-permeant antioxidant and GSH precursor, alleviated oxidative damage and cognitive decline, and restored glutathione synthase and GSH levels in ApoE-deficient mice deprived of folate to those of normal mice maintained in the presence of folate. These data support the administration of antioxidant precursors to buffer oxidative damage in neurodegenerative disorders.

Pages 139-148
Xiao-Ping Shi, Katherine Tugusheva, James E. Bruce, Adam Lucka, Elizabeth Chen-Dodson, Binghua Hu, Guo-Xin Wu, Eric Price, Robert, B. Register, Janet Lineberger, Ron Miller, Mei-Jy Tang, Amy Espeseth, Jason Kahana, Abigail Wolfe, Ming-Chih Crouthamel, Sethu Sankaranarayanan, Adam Simon, Lin Chen, Ming-Tain Lai, Beth Pietrak, Jillian DiMuzio, Yueming Li, Min Xu, Qian Huang, Victor Garsky, Mohinder K. Sardana, Daria J. Hazuda (Communicated by Yuan Luo)
Novel mutations introduced at the ß-site of amyloid precursor protein enhance the production of amyloid ß peptide by BACE1 in vitro and in cells
Abstract: Abnormal production and accumulation of amyloid-ß peptide (Aß) plays a major role in the pathogenesis of Alzheimer’s disease (AD). ß-secretase (BACE1) is responsible for the cleavage at the ß-site in amyloid ß protein precursor (AßPP/APP) to generate the N-terminus of Aß. Here we report the stepwise identification and characterization of a novel APP-ß-site mutant, "NFEV" (APP_NFEV) in vitro and in cells. In vitro, the APP_NFEV exhibits 100-fold enhanced cleavage rate relative to the “wild-type” substrate (APPwt) and 10-fold increase relative to the Swedish-type mutation variant (APPsw). In cells, it was preferably cleaved among 24 APP ß-site mutations tested. More importantly, the APP_NFEV mutant failed to generate any detectable Aß peptides in BACE1-KO mouse fibroblast cells. The production of Aß peptides was restored by co-transfecting human BACE1, demonstrating that BACE1 is the only enzyme responsible for the processing of APP_NFEV in these cells. Analysis of APP_NFEV cleavage products secreted in the media revealed that in cells BACE1 cleaves APP_NFEV at the position between NF and EV, identical to that observed in vitro. A BACE inhibitor blocked the processing of the APP_NFEV ß-site in vitro and in cells. Our data indicates that the "NFEV" mutant is not only an enhanced substrate for BACE1 in vitro, but also a specific substrate for BACE1 in cells.

Pages 149-157
Johannes Attems, Felix Lintner, Kurt A. Jellinger
Olfactory Involvement in Aging and Alzheimer’s Disease: An Autopsy Study
Abstract: Olfactory dysfunction and tau pathology in the olfactory bulb increase with the severity of Alzheimer’s disease. We report data of a postmortem study in the aged. 130 autopsy cases (81 female, 49 male, aged 61-102, mean 82.48±4.35 SD) years, underwent a standardized neuropathological assessment with immunohistochemical study of tau pathology in the olfactory bulb and nerve and of Alzheimer's disease using established criteria including Braak staging. All cases of definite Alzheimer's disease (Braak stages 5 and 6) (n=40) showed large numbers of neuropil threads and neurofibrillary tangles, with amyloid deposits in 32.5% and neuritic plaques in one single case in the olfactory system. Braak stage 4 (n=27) was associated with mild to moderate tau pathology in 85.2%, and amyloid plaques in 1.1%, Braak stage 3 (n=28) with olfactory tau lesions in 37.0% and amyloid deposits in one single case, Braak stages 3 and 4 with olfactory tau lesions in 61.1%. Braak stage 2 (n=15) showed olfactory tau pathology in 31.2%, whereas Braak stages 0 and 1 (n=15) were all negative. The olfactory system tau score showed highly significant correlations with neuritic Braak stages in the brain, while both scores showed significant but low correlations with age. These data confirm previous studies demonstrating abundant tau pathology in the olfactory system in all definite Alzheimer’s disease cases, in two-thirds of limbic Alzheimer’s disease, and in almost one-third of non-demented elderly persons with Braak stage 2. There are strong correlations between tau pathology in the olfactory and limbic systems, both with similar increase in severity. Clinical dementia correlated with both Braak and olfactory system tau scores. Since the involvement of both systems is associated with a high risk of cognitive decline, future studies should validate the sensitivity of olfactory mucosa biopsies in the diagnosis of Alzheimer’s disease.

Pages 159-171
Syed I.A. Zaidi, Sandra L. Richardson, Sabina Capellari, Li Song, Bernardino Ghetti, Man-Sun Sy, Pierluigi Gambetti, Robert B. Petersen
Characterization of the F198S Prion Protein Mutation: Enhanced Glycosylation and Defective Refolding
Abstract: Prion diseases are associated with the accumulation of a misfolded, protease resistant form of the prion protein, PrPres. In humans there are a variety of different prion related diseases that are sporadic, inherited, or acquired by infection. Gerstmann-Straussler-Sheinker syndrome (GSS) is an inherited prion disease in which PrPres accumulates as amorphous aggregates as well as in amyloid plaques. GSS has been associated with a variety of point mutations in the prion protein: 102, 105, 117, 131, 145, 187, 198, 202, 212, 217, and 232. The F198S mutation was discovered in a large Indiana kindred. Previous studies in vitro have shown that the 198 mutation results in structural instability of the prion protein. In the current study, we demonstrate in a cell model that the F198S mutant protein can be folded properly in a cellular context, but is unable to refold to a native state after denaturation. Further, the F198S mutation significantly affects glycosylation of the mutant protein.

Pages 173-180
Transcript: Alzheimer Research Forum Live Discussion
Brain Derived Neurotrophic Factor and Alzheimer's Disease—What Is the Connection?

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