Journal of Alzheimer's Disease - Volume 13, issue 3

Authors: Whitehouse, Peter J.

Article Type: Short Communication

DOI: 10.3233/JAD-2008-13301

Citation: Journal of Alzheimer's Disease, vol. 13, no. 3, pp. 239-240, 2008

Authors: Erol, Adnan

Article Type: Review Article

Abstract: Acquired disturbances of several aspects of cellular metabolism appear pathologically important in sporadic Alzheimer's disease (SAD). Among these, brain glucose utilization is reduced in the early stages of the disease. Hyperinsulinemia, which is a characteristic finding of insulin resistance, results in a central insulin deficit. Insufficient insulin signaling impairs the intricate balance of nitric oxide regulation of the central nervous system. Reduction in central insulin decreases neuronal nitric oxide synthase and increases inducible synthase activity. This, in turn, decreases astrocytic energy substrates and antioxidant supply of neurons. In addition, an increase in peroxynitrite formation impairs redox balance. Hyperleptinemia and glucose …excess, which are the other parameters of insulin resistance, may worsen the reduced astrocytic energy supply and the ongoing inflammation via the inhibition of AMP-activated protein kinase (AMPK). Consequently, energy deficit and inflammation in neuronal tissue may cause neurodegeneration of SAD. Show more

Keywords: Alzheimer's disease, inflammation, insulin resistance, ketone, neurodegeneration

DOI: 10.3233/JAD-2008-13302

Citation: Journal of Alzheimer's Disease, vol. 13, no. 3, pp. 241-253, 2008

Authors: Bekris, Lynn M. | Millard, Steven P. | Galloway, Nichole M. | Vuletic, Simona | Albers, John J. | Li, Ge | Galasko, Douglas R. | DeCarli, Charles | Farlow, Martin R. | Clark, Chris M. | Quinn, Joseph F. | Kaye, Jeffrey A. | Schellenberg, Gerard D. | Tsuang, Debby | Peskind, Elaine R. | Yu, Chang-En

Article Type: Research Article

Abstract: The ε4 allele of the apolipoprotein E gene (APOE) is associated with increased risk and earlier age at onset in late onset Alzheimer's disease (AD). Other factors, such as expression level of apolipoprotein E protein (apoE), have been postulated to modify the APOE related risk of developing AD. Multiple loci in and outside of APOE are associated with a high risk of AD. The aim of this exploratory hypothesis generating investigation was to determine if some of these loci predict cerebrospinal fluid (CSF) apoE levels in healthy non-demented subjects. CSF apoE levels were measured from healthy non-demented subjects 21–87 years …of age (n=134). Backward regression models were used to evaluate the influence of 21 SNPs, within and surrounding APOE, on CSF apoE levels while taking into account age, gender, APOE ε4 and correlation between SNPs (linkage disequilibrium). APOE ε4 genotype does not predict CSF apoE levels. Three SNPs within the TOMM40 gene, one APOE promoter SNP and two SNPs within distal APOE enhancer elements (ME1 and BCR) predict CSF apoE levels. Further investigation of the genetic influence of these loci on apoE expression levels in the central nervous system is likely to provide new insight into apoE regulation as well as AD pathogenesis. Show more

Keywords: Apolipoprotein E gene, apolipoprotein E protein, cerebroshinal fluid, enhancer, promoter, SNP

DOI: 10.3233/JAD-2008-13303

Citation: Journal of Alzheimer's Disease, vol. 13, no. 3, pp. 255-266, 2008

Authors: Rodrigues, Mark A. | Verdile, Giuseppe | Foster, Jonathan K. | Hogervorst, Eva | Joesbury, Karen | Dhaliwal, Satvinder | Corder, Elizabeth H. | Laws, Simon M. | Hone, Eugene | Prince, Richard | Devine, Amanda | Mehta, Pankaj | Beilby, John | Atwood, Craig S. | Martins, Ralph N.

Article Type: Research Article

Abstract: Recent research studies associate elevated gonadotropin levels with dementia. Specifically, an age associated increase in levels of luteinizing hormone has been linked to an increased risk of Alzheimer's disease. The objective of this study was to investigate the association between gonadotropin levels and cognition in older, healthy postmenopausal women. Cognitive functioning was compared with plasma levels of estradiol, luteinizing hormone, follicle stimulating hormone, Aβ40 and APOE genetic status in 649 community-dwelling, non-demented older women residing in Western Australia. High endogenous luteinizing hormone levels were associated with a lower cognitive score, especially in older women and in those women that were …depressed. Unexpectedly, disproportionately well preserved cognitive functioning was found for the oldest women who had high endogenous levels of follicle stimulating hormone. The findings indicate that gonadotropins can impact upon cognitive functioning in older postmenopausal women, and that luteinizing hormone and follicle stimulating hormone may exert contrasting effects. Taken together, the findings have important implications for the development of possible preventive strategies for dementia. Show more

Keywords: Amyloid-β40, APOE, Cambridge Cognitive Examination, estradiol, follicle stimulating hormone, gonadotropin releasing hormone, luteinizing hormone

DOI: 10.3233/JAD-2008-13304

Citation: Journal of Alzheimer's Disease, vol. 13, no. 3, pp. 267-274, 2008

Authors: Alvarez, Victoria | Corao, Ana I. | Alonso-Montes, Cristina | Sánchez-Ferrero, Elena | De Mena, Lorena | Morales, Blanca | García-Castro, Mónica | Coto, Eliecer

Article Type: Research Article

Abstract: Impaired mitochondrial function and an increased number of mutations in mitochondrial DNA (mtDNA) has been found in brains of patients with late-onset Alzheimer's disease (LOAD). The TFAM-gene encodes the mitochondrial transcription factor A, a protein that controls the transcription, replication, damage sensing, and repair of mtDNA. TFAM is on human chromosome region 10q21.1, where a locus for LOAD has been mapped. Our objective was to determine the role of TFAM-gene variation in the risk of LOAD. The seven TFAM coding exons were analysed through single strand conformation analysis and direct sequencing in a cohort of Spanish LOAD-patients and healthy controls. …We found four common polymorphisms, two in the flanquing intronic and two in the coding sequences. Polymorphism rs1937 (+35 G/C) was the only missense change (S12T). Genotyping of this polymorphism in 300 LOAD-patients and 183 healthy controls showed a significantly higher frequency of GG-homozygotes in the patients (92% vs. 86%; p=0.04; OR=1.91, 95%CI=1.02–3.50). This suggests that S12 is a risk factor for LOAD in our population. In conclusion, rare variants (mutations) in the TFAM gene were not found in LOAD-patients, but the S12T polymorphism was a moderate risk factor for LOAD in our population. Show more

Keywords: Alzheimer's disease, genetic association, gene variation, mitochondria transcription factor

DOI: 10.3233/JAD-2008-13305

Citation: Journal of Alzheimer's Disease, vol. 13, no. 3, pp. 275-280, 2008

Authors: Hübinger, Gabriele | Geis, Silvia | LeCorre, Sylvie | Mühlbacher, Susanne | Gordon, Sandra | Fracasso, R. Paul | Hoffman, Fred | Ferrand, Sandrine | Klafki, Hans W. | Roder, Hanno M.

Article Type: Research Article

Abstract: Abnormal hyperphosphorylation of tau is believed to constitute a critical biochemical event in the process of neurofibrillary degeneration of Alzheimer's disease. We have developed a cellular model where apparently authentic PHF-like tau hyperphosphorylation is induced by okadaic acid. To gain deeper insight into the complex mechanisms of this pathological process we tested a variety of kinase inhibitors in this model. We found that K252a is differentiated from staurosporine by its inhibition of ERK2: both compounds are structurally related microbial metabolites generally believed to have only moderate kinase selectivity. However, since ERK2 inhibitors are exceedingly rare, we used this differential inhibitory …property of K252a to demonstrate the involvement of ERK2 in PHF-type tau hyperphosphorylation. K252a was uniquely able to completely suppress the okadaic acid-induced tau hyperphosphorylation in SH-SY5Y cells and rat brain slices by way of including ERK2 in its inhibitory spectrum, and to conserve the normal binding of tau to tubulin. GSK3 inhibitors partially affected the normal state of tau phosphorylation in SH-SY5Y cells, but had no impact on okadaic acid-induced tau hyperhosphorylation. As K252a is the first molecule identified capable of preventing the spectrum of PHF-like tau hyperphosphorylation markers, it may represent a conceptual starting point for therapeutic development of suitable spectrum kinase inhibitors. Show more

Keywords: Alzheimer's disease, ERK2 inhibitor, K252a, PHF, tau hyperphosphorylation

DOI: 10.3233/JAD-2008-13306

Citation: Journal of Alzheimer's Disease, vol. 13, no. 3, pp. 281-294, 2008

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

Article Type: Research Article

Abstract: Virtually all individuals with Down syndrome (DS) develop neurofibrillary tangles, a characteristic brain lesion of Alzheimer's disease (AD), when they reach the fourth decade of life. In AD, neurofibrillary tangles are thought to result from abnormal hyperphosphorylation of tau protein, which, in turn, can result from down-regulation of protein phosphatase (PP) 2A, a major brain tau phosphatase. The abnormal hyperphosphorylation of tau in DS had not yet been characterized, and its causes were not understood. In this study, by using quantitative Western blot analysis, we found that the level of the catalytic subunit of PP2A, but not of PP1, PP2B …or PP5, was dramatically decreased. The decrease of PP2A level correlated negatively to tau level and tau phosphorylation at several abnormal hyperphosphorylation sites, including Ser199, Thr205, Thr212, Ser262, Ser396 and Ser422. Our results indicate that PP2A is down-regulated in DS brain and suggest that this down-regulation might be involved in the abnormal hyperphosphorylation and accumulation of tau. Show more

Keywords: Alzheimer disease, Down syndrome, hyperphosphorylation, Protein phosphatases, tau

DOI: 10.3233/JAD-2008-13307

Citation: Journal of Alzheimer's Disease, vol. 13, no. 3, pp. 295-302, 2008

Authors: Boldogh, Istvan | Kruzel, Marian L.

Article Type: Review Article

Abstract: Colostrum-derived proline-rich polypeptide, also known as Colostrinin™ (CLN), has been shown to have a stabilizing effect on cognitive function in Alzheimer's disease patients. This complex action of CLN could be related to prevention of amyloid-β peptide aggregation, as shown in in vitro studies, and its impact on delicate cassettes of signaling pathways common to cellular redox regulation, proliferation and differentiation. Studies on cultured cells showed that CLN modulates intracellular levels of reactive oxygen species (ROS), via regulation of glutathione metabolism, activity of antioxidant enzymes and mitochondria function. Due to an improvement in senescence-associated mitochondrial dysfunction and a decrease in ROS …generation, CLN decelerates the aging processes of both cultured cells and experimental animals. When given orally to mice, CLN increased the lifespan and improved various motor and sensory activities. Although the molecular basis by which CLN exerts its diverse effects are still under investigation, the regulatory effect on the cellular redox state via maintenance of mitochondrial function and modification of ROS-induced cell signaling seem to be of great importance. In this article, we examine experimental data pertinent to the mechanism of action, including a review of CLN's utility in the maintenance of physiological processes in which oxidative stress has an etiological role. Show more

Keywords: Age-related disorders, Alzheimer's disease, amyloid-β, immunomodulation, oxidative stress, proline-rich polypeptide

DOI: 10.3233/JAD-2008-13308

Citation: Journal of Alzheimer's Disease, vol. 13, no. 3, pp. 303-321, 2008

Authors: Reger, Mark A. | Watson, G. Stennis | Green, Pattie S. | Baker, Laura D. | Cholerton, Brenna | Fishel, Mark A. | Plymate, Stephen R. | Cherrier, Monique M. | Schellenberg, Gerard D. | Frey II, William H. | Craft, Suzanne

Article Type: Research Article

Abstract: Intranasal insulin administration raises central nervous system (CNS) insulin levels in humans and acutely facilitates verbal memory in patients with Alzheimer's disease (AD), an effect that may differ by APOE genotype. The purpose of this study was to examine the cognitive dose response curves for intranasal insulin administration, and determine whether the effects of insulin differ between participants with (ε4+) and without (ε4−) the APOE- ε4 allele. On separate mornings, 33 memory-impaired adults with AD or amnestic mild cognitive impairment and 59 normal adults each underwent five intranasal treatment conditions consisting of insulin (10, 20, 40, or 60 IU) or …placebo. Cognition was tested 15-minutes post-treatment, and blood was acquired at baseline and 45-minutes post-treatment. Plasma insulin and glucose levels were unaffected by treatment. Insulin administration facilitated recall on two measures of verbal memory in memory-impaired ε4− adults, with performance generally peaking at 20 IU. In contrast, memory-impaired ε4+ subjects demonstrated a relative decline in verbal memory. Insulin also differentially modulated plasma amyloid-β for memory-impaired subjects and normal controls, effects that again differed by APOE genotype. These findings suggest that groups with different genetic risks for AD may show differential dose-response curves following intranasal insulin administration. Show more

Keywords: Alzheimer's disease, amyloid-β, insulin, intranasal administration, memory, mild cognitive impairment

DOI: 10.3233/JAD-2008-13309

Citation: Journal of Alzheimer's Disease, vol. 13, no. 3, pp. 323-331, 2008

Authors: Bruandet, Amélie | Richard, Florence | Tzourio, Christophe | Berr, Claudine | Dartigues, Jean-François | Alpérovitch, Annick | Amouyel, Philippe | Helbecque, Nicole

Article Type: Research Article

Abstract: The purpose of this study was to examine the impact of two polymorphisms (rs4291A>T and rs4343G>A) in the ACE gene on the risk of Alzheimer's disease (AD), using a population-based cohort of 9294 subjects selected from the electoral rolls of three French cities (the Three-City Study). Two follow-up examinations took place 2 and 4 years after inclusion. Diagnosis of dementia was assessed at baseline and at each follow-up examination by neurologists independent of the 3C Study group. For the present analysis, subjects whose mother tongue was not French, those from abroad and those lost at follow-up were excluded, leaving a …sample of 6791 subjects. 108 subjects were demented at baseline and 216 subjects, among which 141 had AD, developed a dementia during follow-up. The genotype distributions of the ACE SNPs rs4291 and rs4343 did not differ according to cognitive status. After adjustment for confounding variables, the risk of developing AD was similar whatever the genotype (rs4291 AT vs TT: OR=0.90, p=0.65; AA vs TT: OR=1.05, p= 0.84; rs4343 GA vs GG: OR=1.15, p= 0.48; AA vs GG: OR=1.25, p= 0.37). No global haplotype effect could be observed on the risk of AD. Show more

Keywords: Alzheimer's disease, case-control study, genetics, polymorphism, risk factors

DOI: 10.3233/JAD-2008-13310

Citation: Journal of Alzheimer's Disease, vol. 13, no. 3, pp. 333-339, 2008