Volume 13, Number 3, April 2008

Pages 239-240
Commentary
   Peter J. Whitehouse
   National Institutes of Health and Clinical Excellence decision processes supported by UK High Court: The debate about the value of Alzheimer's disease drugs continues

Pages 241-253
Adnan Erol
An integrated and unifying hypothesis for the metabolic basis of sporadic Alzheimer’s disease
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 characteristic finding of insulin resistance, reasons in central insulin deficit. Insufficient insulin signaling impairs the intricate balance of nitric oxide regulation of central nervous system. Reduction in central insulin decreases neuronal nitric oxide synthase and increases inducible synthase activity. This, in turn, decreases energy substrates and antioxidant supplies of astrocyte to neuron. In addition, increase in peroxynitrite formation impairs redox balance. Hyperleptinemia and glucose excess, which are the other parameters of insulin resistance, may worsen the decrease of 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.

Pages 255-266
Lynn M. Bekris, Steven P. Millard, Nichole M. Galloway, Simona Vuletic, John J. Albers, Ge Li, Douglas R. Galasko, Charles DeCarli, Martin R. Farlow, Chris M. Clark, Joseph F. Quinn, Jeffrey A. Kaye, Gerard D. Schellenberg, Debby Tsuang, Elaine R. Peskind, Chang-En Yu (Communicated by Thomas Montine)
Multiple SNPs within and surrounding the Apolipoprotein E Gene Influence Cerebrospinal Fluid Apolipoprotein E Protein Levels
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.

Pages 275-280
Mark A. Rodrigues, Giuseppe Verdile, Jonathan K. Foster, Eva Hogervorst, Karen Joesbury, Satvinder Dhaliwal, Elizabeth H. Corder, Simon M. Laws, Eugene Hone, Richard Prince, Amanda Devine, Pankaj Mehta, John Beilby, Craig S. Atwood , Ralph N. Martins
Gonadotropins and Cognition in Older Women
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 six hundred and forty-nine 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.

Pages 281-294
Victoria Alvarez, Ana I. Corao, Cristina Alonso-Montes, Elena Sánchez-Ferrero, Lorena De Mena, Blanca Morales, Mónica García-Castro, Eliecer Coto (Communicated by Alessandro Serretti)
Mitochondrial transcription factor A (TFAM) gene variation and risk of late-onset Alzheimer’s disease
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-geneencodes the mitochondrial transcription factor A, a protein that controls the transcription, replication, damage sensing, and repair of mtDNA. TFAMis on human chromosome region 10q21.1, where a locus for LOAD has been mapped. Our objective was to determine the role of TFAM-genevariation in the risk of LOAD. The seven TFAMcoding 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.

Pages 295-302
Gabriele Hübinger, Silvia Geis, Sylvie LeCorre, Susanne Mühlbacher, Sandra Gordon, R. Paul Fracasso, Fred Hoffman, Sandrine Ferrand, Hans W. Klafki, Hanno M. Roder
Inhibition of PHF-like Tau Hyperphosphorylation in SH-SY5Y Cells and Rat Brain Slices by K252a
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.

Pages 303-321
Zhihou Liang, Fei Liu, Khalid Iqbal, Inge Grundke-Iqbal, Jerzy Wegiel, Cheng-Xin Gong (Communicated by Xiongwei Zhu)
Decrease of protein phosphatase 2A and its association with accumulation and hyperphosphorylation of tau in Down syndrome
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.

Pages 323-331
Istvan Boldogh, Marian L. Kruzel (Communicated by Thamarapu Srikrishnan)
Colostrinin™: An Oxidative Stress Modulator for Prevention and Treatment of Age-Related Disorders
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 (AD) 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 regulating 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 life-span 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.

Pages 323-331
Mark A. Reger, G. Stennis Watson, Pattie S. Green, Laura D. Baker, Brenna Cholerton, Mark A. Fishel, Stephen R. Plymate, Monique M. Cherrier, Gerard D. Schellenberg, William H. Frey II, Suzanne Craft
Intranasal Insulin Administration Dose-Dependently Modulates Verbal Memory and Plasma Amyloid-β in Memory-Impaired Older Adults
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.

Pages 333-339
Amélie Bruandet, Florence Richard, Christophe Tzourio, Claudine Berr, Jean-François Dartigues, Annick Alpérovitch, Philippe Amouyel, Nicole Helbecque (Communicated by Francesco Panza)
Haplotypes across ACE and the risk of Alzheimer’s disease: The Three-City Study
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 ACESNPs 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.

Pages 341-349
Yanan Xu, Zhiming Cao, Ikhlas Khan, Yuan Luo
Gotu Kola (Centella Asiatica) Extract Enhances Phosphorylation of Cyclic AMP Response Element Binding Protein in Neuroblastoma Cells Expressing Amyloid-β Peptide
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that shows cognitive deficits and memory impairment. Extract from the leaves of Gotu Kola (Centella Asiatica) have been used as an alternative medicine for memory improvement in Indian Ayurvedic system of medicine for a long time. Although several studies have revealed its effect in ameliorating the cognitive impairment in rat models of AD and stimulating property on neuronal dendrites of hippocampal region, the molecular mechanism of Gotu Kola on neuroprotection still remains to be elucidated. In this study, we report that phosphorylation of cyclic AMP response element binding protein (CREB) is enhanced in both a neuroblastoma cell line expressing amyloid-β 1-42 (Aβ) and in rat embryonic cortical primary cell culture. In addition, the contribution of two major single components to the enhanced CREB phosphorylatioin was examined. Furthermore, inhibitors were applied in this study revealing that ERK/RSK signaling pathway might mediate this effect of Gotu Kola extract. Taken together, we provide a possible molecular mechanism for memory enhancing property of Gotu Kola extract for the first time.

Page 351
Book Review: A Personal Guide to Living with Progressive Memory Loss, by Sandy Burfener and Prudence Twigg, Jessica Kingsley Publishers, London, UK, 2007, 160 pp. Reviewed by Alan J. Lerner.

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