Journal of Alzheimer's Disease - Volume 8, issue 3

Authors: del C. Alonso, Alejandra | Iqbal, Khalid

Article Type: Research Article

DOI: 10.3233/JAD-2005-8301

Citation: Journal of Alzheimer's Disease, vol. 8, no. 3, pp. 223-226, 2005

Authors: Soreghan, Brian A. | Lu, Bing-Wen | Thomas, Stefani N. | Duff, Karen | Rakhmatulin, Eugene A. | Nikolskaya, Tatiana | Chen, Ting | Yang, Austin J.

Article Type: Research Article

Abstract: Increasing evidence suggests that oxidative injury is involved in the pathogenesis of many age-related neurodegenerative disorders, including Alzheimer's disease (AD). Identifying the protein targets of oxidative stress is critical to determine which proteins may be responsible for the neuronal impairments and subsequent cell death that occurs in AD. In this study, we have applied a high-throughput shotgun proteomic approach to identify the targets of protein carbonylation in both aged and PS1+AβPP transgenic mice. However, because of the inherent difficulties associated with proteomic database searching algorithms, several newly developed bioinformatic tools were implemented to ascertain a probability-based discernment between correct protein …assignments and false identifications to improve the accuracy of protein identification. Assigning a probability to each identified peptide/protein allows one to objectively monitor the expression and relative abundance of particular proteins from diverse samples, including tissue from transgenic mice of mixed genetic backgrounds. This robust bioinformatic approach also permits the comparison of proteomic data generated by different laboratories since it is instrument- and database-independent. Applying these statistical models to our initial studies, we detected a total of 117 oxidatively modified (carbonylated) proteins, 59 of which were specifically associated with PS1+AβPP mice. Pathways and network component analyses suggest that there are three major protein networks that could be potentially altered in PS1+AβPP mice as a result of oxidative modifications. These pathways are 1) iNOS-integrin signaling pathway, 2) CRE/CBP transcription regulation and 3) rab-lyst vesicular trafficking. We believe the results of these studies will help establish an initial AD database of oxidatively modified proteins and provide a foundation for the design of future hypothesis driven research in the areas of aging and neurodegeneration. Show more

Keywords:

DOI: 10.3233/JAD-2005-8302

Citation: Journal of Alzheimer's Disease, vol. 8, no. 3, pp. 227-241, 2005

Authors: Odetti, Patrizio | Piccini, Alessandra | Giliberto, Luca | Borghi, Roberta | Natale, Alessia | Monacelli, Fiammetta | Marchese, Monica | Assini, Andrea | Colucci, Monica | Cammarata, Sergio | Tabaton, Massimo

Article Type: Research Article

Abstract: Epidemiological and experimental data suggest that type 2 diabetes (DM2) and sporadic late-onset Alzheimer's disease (AD) share a common mechanism, that is able to produce accumulation of insulin and amyloid β42 (Aβ42), the major pathogenic events respectively of the two conditions. In 71 non diabetic patients with amnestic mild cognitive impairment we found a significant linear correlation between fasting plasma levels of insulin and Aβ42 (R=+0.25, P<0.05). The levels of both peptides were elevated in comparison to 48 age-matched cognitively normal controls. The correlation of insulin and Aβ42 plasma levels suggests a pathogenic link between DM2 and sporadic AD.

Keywords: Amyloid β42, insulin, Alzheimer's disease, type 2 diabetes, mild cognitive impairment

DOI: 10.3233/JAD-2005-8303

Citation: Journal of Alzheimer's Disease, vol. 8, no. 3, pp. 243-245, 2005

Authors: Rivera, Enrique J. | Goldin, Alison | Fulmer, Noah | Tavares, Rose | Wands, Jack R. | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: Reduced glucose utilization and energy metabolism occur early in the course of Alzheimer's disease (AD) and correlate with impaired cognition. Glucose utilization and energy metabolism are regulated by insulin and insulin-like growth factor I (IGF-I), and correspondingly, studies have shown that cognitive impairment may be improved by glucose or insulin administration. Recently, we demonstrated significantly reduced levels of insulin and IGF-I polypeptide genes and their corresponding receptors in advanced AD relative to aged control brains. The abnormalities in gene expression were accompanied by impaired survival signaling downstream through PI3 kinase-Akt. The present work characterizes the abnormalities in insulin and IGF …gene expression and receptor binding in brains with different Braak stage severities of AD. Realtime quantitative RT-PCR analysis of frontal lobe tissue demonstrated that increasing AD Braak Stage was associated with progressively reduced levels of mRNA corresponding to insulin, IGF-I, and IGF-II polypeptides and their receptors, tau, which is regulated by insulin and IGF-I, and the Hu D neuronal RNA binding protein. In contrast, progressively increased levels of amyloid β protein precursor (AβPP), glial fibrillary acidic protein, and the IBA1/AIF1 microglial mRNA transcripts were detected with increasing AD Braak Stage. Impairments in growth factor and growth factor receptor expression and function were associated with increasing AD Braak stage dependent reductions in insulin, IGF-I, and IGF-II receptor binding, ATP levels, and choline acetyltransferase (ChAT) expression. Further studies demonstrated that: 1) ChAT expression increases with insulin or IGF-I stimulation; 2) ChAT is expressed in insulin and IGF-I receptor-positive cortical neurons; and 3) ChAT co-localization in insulin or IGF-I receptor-positive neurons is reduced in AD. Together, these data provide further evidence that AD represents a neuro-endocrine disorder that resembles a unique form of diabetes mellitus (? Type 3) and progresses with severity of neurodegeneration. Show more

Keywords: Insulin resistance, insulin gene expression, central nervous system, Alzheimer's disease, growth factor receptors, real time RT-PCR, Type 3 diabetes

DOI: 10.3233/JAD-2005-8304

Citation: Journal of Alzheimer's Disease, vol. 8, no. 3, pp. 247-268, 2005

Authors: Balakrishnan, Kelvin | Verdile, Giuseppe | Mehta, Pankaj D. | Beilby, John | Nolan, David | Galvão, Daniel A. | Newton, Robert | Gandy, Samuel E. | Martins, Ralph N.

Article Type: Research Article

Abstract: Obesity and overweight, well known risk factors for cardiovascular disease and type 2 diabetes, are now associated with Alzheimer's disease (AD). It remains to be determined if obesity and overweight contribute to the risk of developing AD through modulating levels of amyloid-beta (Aβ), a key molecule in AD pathogenesis. Thus, we investigated whether there were any associations between plasma Aβ levels and body mass index (BMI) or fat mass (FM) in a group of 18 healthy adults. A statistically significant correlation was found between BMI, FM, and plasma levels of Aβ42 (BMI r= 0.602, P=0.008; FM r= 0.547, P=0.019), the …longer, more pathogenic form of Aβ, but not with plasma levels of the shorter, less pathogenic Aβ40. Although not significant, positive correlations between plasma levels of Aβ42 and levels of insulin and the inflammatory marker C-reactive protein (CRP), along with an inverse trend between plasma Aβ42 levels and levels of high density lipoprotein (HDL) were answered. These results suggest that proteins implicated in inflammation, cardiovascular disease and type 2 diabetes, which in turn are risk factors for AD, may contribute to the associations between BMI/FM and plasma Aβ42 levels. Longitudinal studies involving larger cohorts are required to determine if elevated body fat may predispose individuals to AD through increasing Aβ42 levels throughout early to late adulthood. Show more

DOI: 10.3233/JAD-2005-8305

Citation: Journal of Alzheimer's Disease, vol. 8, no. 3, pp. 269-282, 2005

Authors: Tchantchou, Flaubert | Chan, Amy | Kifle, Lydia | Ortiz, Daniela | Shea, Thomas B.

Article Type: Research Article

Abstract: Oxidative stress contributes to age-related cognitive decline. In some instances, consumption of fruits and vegetables rich in antioxidant can provide superior protection than supplementation with purified antioxidants. Our prior studies have shown that supplementation with apple juice concentrate (AJC) alleviates oxidative damage and cognitive decline in a transgenic murine model compromised in endogenous antioxidant potential when challenged with a vitamin-deficient, oxidative stress-promoting diet. Herein, we demonstrate that AJC, administered in drinking water, is neuroprotective in normal, aged mice. Normal mice aged either 9–10 months or 2–2.5 years were maintained for 1 month on a complete diet or a diet lacking …folate and vitamin E and containing iron as a pro-oxidant, after which oxidative damage was assayed by thiobarbituric acid-reactive substances and cognitive decline as assayed by performance in a standard Y-maze. Mice 9–12 months of age were unaffected by the deficient diet, while older mice demonstrated statistically-increased oxidative damage and poorer performance in a Y maze test. Supplementation with AJC prevented these neurodegenerative effects. These data are consistent with normal aged individuals being susceptible to neurodegeneration following dietary compromise such as folate deficiency, and a hastened onset of neurodegeneration in those individuals harboring a genetic risk factor such as ApoE deficiency. These findings also support the efficacy of antioxidant supplementation, including consumption of antioxidant-rich foods such as apples, in preventing the decline in cognitive performance that accompanies normal aging. Show more

Keywords: Aging, neurodegeneration, antioxidants, cognitive decline, nutrition, apple juice

DOI: 10.3233/JAD-2005-8306

Citation: Journal of Alzheimer's Disease, vol. 8, no. 3, pp. 283-287, 2005

Authors: Menendez-Gonzalez, Manuel | Calatayud, Maria Teresa | Blazquez-Menes, Bernardino

Article Type: Research Article

Abstract: Introduction: Lewy body dementia (DLB) is common but frequently misdiagnosed as Alzheimer’s disease plus delirium or parkinsonism. Drugs used in this disorder can cause exacerbations: neuroleptic medication is relatively contraindicated because some patients show severe neuroleptic sensitivity, antiparkinsonian medication has the potential to exacerbate psychotic symptoms, and even cholinesterase inhibitors, while relatively safe, have provoked adverse responses in some DLB patients. There are few data available about the use of memantine in DLB. Case presentation: A 74-year-old man was diagnosed with Alzheimer disease and parkinsonism. After memantine was started he developed severe fluctuations in awareness, visual hallucinations, agitation, …and worsened parkinsonism. When he was evaluated thoroughly, the diagnosis was revised to Lewy body dementia, leading to changes in treatment that were associated with dramatic improvement in the patient’s mental status. Conclusions: In our patient, motor and cognitive symptoms worsened with memantine treatment; these resolved after memantine was discontinued. Show more

Keywords: Lewy bodies dementia, memantine, exacerbation, visual hallucinations, parkinsonism

DOI: 10.3233/JAD-2005-8307

Citation: Journal of Alzheimer's Disease, vol. 8, no. 3, pp. 289-291, 2005

Authors: Kaur, M. | Balgir, P.P.

Article Type: Research Article

Abstract: Objective: To investigate the association between APOE genotypes and Alzheimer’s disease (AD) in elderly Indian subjects. The study also aims at the identification of consanguinity as disease risk factor for AD. Methods: A total of 100 Indian patients (26 consanguineous, 74 non-consanguineous), meeting criteria for probable or definite AD and 36 cognitively healthy, elderly unrelated control subjects (spouses), were included in the study. The APOE genotyping and statistical analyses (SPSS 7.5) was performed to determine the odds of AD according to APOE genotype. Results: The analysis revealed increased prevalence of E4 allele in patients as compared …with controls. The difference in prevalence of E3 and E4 alleles was found to be statistically significant between consanguineous patients and controls as well as non-consanguineous patients and controls. Compared to individuals with the APOE3/3, the odds of having AD were significantly increased among those with one or more copies of the E4 allele, even after adjusting with age and sex. An interesting outcome of the study is the higher prevalence of the E2 allele in consanguineous AD patients (in contrast to previously reported studies). The risk for AD was higher in consanguineous individuals with E2/4 genotype (1.62 fold), as compared to non-consanguineous individuals. Discussion: The Results support that the APOE4 allele plays a role as a risk factor for AD and suggests that the APOE2 allele may not play a protective role in the development of AD in Indians, especially individuals with family history of consanguinity. The study hypothesises that the consanguinity modifies the disease risk associated with E2 allele, although this allele is considered protective. The less number of subjects from a broader population limits the study. The wide-ranging population and ethnicity-based studies in the most inbred groups of the world may provide comprehensive insight into this conclusion. Show more

Keywords: Consanguinity, Alzheimer's disease, odds ratios, APOE polymorphism, Indian population

DOI: 10.3233/JAD-2005-8308

Citation: Journal of Alzheimer's Disease, vol. 8, no. 3, pp. 293-297, 2005

Authors: Fukui, Koji | Takatsu, Hirokatsu | Shinkai, Tadashi | Suzuki, Shozo | Abe, Kouichi | Urano, Shiro

Article Type: Research Article

Abstract: To elucidate whether oxidative stress induces cognitive deficit, and whether nerve cells in the hippocampus, which modulates learning and memory functions in the brain, are damaged by oxidative stress and during aging, the influence of hyperoxia as oxidative stress on either the cognitive function of rats or the oxidative damage of nerve cells was investigated. Young rats showed better learning ability than both old rats and vitamin E-deficient young rats. Vitamin E- supplemented young rats showed similar ability to young control rats. After they learned the location of the platform in the Morris water maze test, the young rats and …vitamin E-supplemented young rats were subjected to oxidative stress for 48 h, and the old rats and vitamin E-deficient young rats were kept in normal atmosphere. The memory function of the old rats and vitamin E-deficient young rats declined even when they were not subjected to oxidative stress for 48 h. In contrast, the young rats maintained their memory function for 4 days after the oxidative stress. However, their learning abilities suddenly declined toward that of the normal old rats after 5 days. At this point, nerve cell loss and apoptosis were observed in the hippocampal CA 1 region of young rats. Vitamin E-supplementation in the young rats prevented either memory deficit or the induction of delayed-type apoptosis. The old rats and vitamin E-deficient young rats kept in normal atmosphere for 48 h also showed apoptosis in the hippocampus. Also, 10 days after oxidative stress, amyloid β-like substances appeared in the CA-1 region of control young rats; these substances were also observed in the CA-1 region of the old rats and vitamin E- deficient young rats. These results suggest that reactive oxygen species (ROS) generated by oxidative stress induced amyloid β-like substances and delayed-type apoptosis in the rat hippocampus, resulting in cognitive deficit. Since amyloid β in Alzheimer's disease characterized by cognitive deficit induces neuronal cell death, it is reasonable to consider that amyloid β deposition in the brain may be associated with memory dysfunction. The results of this study imply that age-related hippocampal neuronal damage is prevented by vitamin E supplementation due to the antioxidant effect of vitamin E. Show more

Keywords: Delayed-type apoptosis, oxidative stress, aging, amyloid β, hippocampus, cognitive deficit, learning, memory, vitamin E

DOI: 10.3233/JAD-2005-8309

Citation: Journal of Alzheimer's Disease, vol. 8, no. 3, pp. 299-309, 2005

Article Type: Discussion

DOI: 10.3233/JAD-2005-8310

Citation: Journal of Alzheimer's Disease, vol. 8, no. 3, pp. 311-315, 2005