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  JOURNAL OF ALZHEIMER'S DISEASE

an IOS Press publication

CONTENTS/ABSTRACTS

 PDFs of all articles are available from IOS Press. 

F O R   A U T H O R S

VOLUMES 1-18

VOLUME 19

VOLUME 20

VOLUME 21

VOLUME 22

VOLUME 23

VOLUME 24

VOLUME 25

VOLUME 26

VOLUME 27

VOLUME 28

VOLUME 29

VOLUME 30

VOLUME 31

VOLUME 32

VOLUME 33

VOLUME 34

VOLUME 35

VOLUME 36

The Journal of Alzheimer's Disease is published by IOS Press. ©1998-2012 Journal of Alzheimer's Disease

JAD - Volume 17, Number 2

Volume 17, Number 2, June 2009

Page 243
Letter to the Editor

J. Michael Ryan, Michael Grundman
Anti-Amyloid-β Immunotherapy in Alzheimer’s Disease: ACC-001 Clinical Trials are Ongoing

Pages 245-257
Review Article

Stuart Bennett, Melissa M Grant, Sarah Aldred
Oxidative Stress in Vascular Dementia and Alzheimer’s Disease: A Common Pathology
Abstract: Alzheimer’s disease and vascular dementia are the two most common types of dementia with the former being the most predominant. It is evident that oxidative stress, an environment where pro-oxidant species overwhelm antioxidant species, is involved in the pathogenesis of both forms of dementia. An increased level of reactive oxygen species in the vasculature, reduced nitric oxide bioavailability, and endothelial dysfunction leading to vascular disease is associated with vascular dementia. In Alzheimer’s disease, an increased amount of amyloid-β peptide induces elevated reactive oxygen species production thereby causing neuronal cell death and damage. The recent observation that increased atherosclerotic plaque formation is present in the main artery to the brain in Alzheimer’s disease, coupled with the association of vascular risk factors with this disease, suggests a link between these two dementias. This review will argue that Alzheimer’s disease and vascular dementia are two extremes of one disease, thus assuming a hypothesis where the clinical conditions referred to as dementia are part of a continuum. We propose that the majority of cases share a vascular pathology and that oxidative stress is central to this common pathology.

Pages 259-265
Review Article

Andrew J. Larner, Mark Doran
Genotype-Phenotype Relationships of Presenilin-1 Mutations in Alzheimer’s Disease: An Update
Abstract: It is now more than ten years since pathogenic mutations were first described in the gene encoding presenilin 1 (PSEN1) on chromosome 14. Although PSEN1 mutations are “deterministic” for Alzheimer’s disease, they are associated with marked heterogeneity in the clinical expression of neurological features. We review recent publications on the clinical neurological phenotype of PSEN1 mutations, many of which now appear only in abstracts or brief communications, perhaps because PSEN1 mutations are no longer regarded as “novel”. However, the clinical heterogeneity associated with these mutations prompts important questions about possible genetic and epigenetic factors which may modify disease phenotype. This area, which may also be relevant to neurodegenerative disorders resulting from other genetic mutations, such as those in the tau gene, currently remains ill-understood.

Pages 267-276
Review Article

Adnan Erol
Unraveling the Molecular Mechanisms Behind the Metabolic Basis of Sporadic Alzheimer’s Disease
Abstract: Peripheral insulin resistance is associated with hyperinsulinemia, which may be associated with brain insulin deficiency that is characteristic of sporadic Alzheimer’s disease (sAD). Oxidative insult, which is the result of insulin associated disordered brain energy metabolism, is a significant early event in the pathological cascade of sAD. Aggregation of disease-specific proteins such as amyloid-β and tau may act as a compensatory response against the oxidative insult at the early periods. In the later stages, oxidative stress stimulates c-Jun N-terminal kinase (JNK) activation. The deficient insulin signaling is ultimately linked to protein kinase B (Akt) pathway and subsequently glycogen synthase kinase-3 (GSK3) and forkhead transcription factors (FOXO). Peripheral insulin resistance related intense interactions between JNK, GSK3, FOXO factors, and p53, which may lead to apoptotic neuronal death, are outlined in a postulate. In light of this postulate, the importance of detailed knowledge of these common physiological processes for the opportunities of treatment that could prevent or reduce the onset of sAD is discussed as well.

Pages 277-279
Short Communication

Robert P. Friedland, Robert B. Petersen, Richard Rubenstein
Bovine Spongiform Encephalopathy and Aquaculture
Abstract: Dietary consumption of fish is widely recommended because of the beneficial effects of omega-3 polyunsaturated fatty acids on the risks of cardiovascular and Alzheimer’s diseases. The American Heart Association currently recommends eating at least two servings of fish per week. We are concerned that consumption of farmed fish may provide a means of transmission of infectious prions from cows with bovine spongiform encephalopathy to humans, causing variant Creutzfeldt Jakob disease.

Pages 281-294
Joel Kooistra, Julijana Milojevic, Giuseppe Melacini, Joaquin Ortega (Communicated by Jesus Avila)
A New Function of Human HtrA2 as an Amyloid-β Oligomerization Inhibitor
Abstract: Human HtrA2 is part of the HtrA family of ATP-independent serine proteases that are conserved in both prokaryotes and eukaryotes and localizes to the intermembrane space of the mitochondria. Several recent reports have suggested that HtrA2 is important for maintaining proper mitochondrial homeostasis and may play a role in Alzheimer’s disease (AD), which is characterized by the presence of aggregates of the amyloid-β peptide 1-42 (Aβ1-42). In this study, we analyzed the ability of HtrA2 to delay the aggregation of the model substrate citrate synthase (CS) and of the toxic Aβ1-42 peptide. We found that HtrA2 had a moderate ability to delay the aggregation of CS in vitro, and this activity was significantly enhanced when the PDZ domain was removed suggesting an inhibitory role for this domain on the activity. Additionally, using electron microscopy and nuclear magnetic resonance analyses, we observed that HtrA2 significantly delayed the aggregation of the Aβ1-42 peptide. Interestingly, the protease activity of HtrA2 and its PDZ domain were not essential for the delay of Aβ1-42 peptide aggregation. These results indicate that besides its protease activity, HtrA2 also performs a chaperone function and suggest a role for HtrA2 in the metabolism of intracellular Aβ and in AD.

Pages 295-304
Lili Wang, Shengli Xu, Xianhao Xu, Piu Chan (Communicated by Xiongwei Zhu)
 (-)-Epigallocatechin-3-Gallate Protects SH-SY5Y Cells Against 6-OHDA-Induced Cell Death through STAT3 Activation
Abstract: As a natural product, (-)-Epigallocatechin-3-gallate (EGCG), has demonstrated remarkable neuronal protection by depressing oxidative stress in Parkinson’s disease (PD). However, the molecular mechanisms underlying EGCG neuronal protection have not been clarified. Using 6-hydroxydopamine (6-OHDA)-treated human neuroblastoma SH-SY5Y cells as a PD cell model, we found that 6-OHDA can cause neuronal death by regulating the activity of STAT3. Pretreatment of SH-SY5Y cells with EGCG (0.1-10 μM) significantly attenuated the cell death induced by 6-OHDA. In addition, the STAT3 activity decline induced by 6-OHDA in SH-SY5Y cells can be completely prevented by the presence of 1 μM of EGCG, and neuronal cell proliferation can be stimulated by EGCG treatment. These results clearly demonstrate that the disruption of STAT3 signaling by 6-OHDA makes significant contribution to the neuronal death in PD, and the protection of EGCG on neurons against oxidative stress-induced cell death may result from the re-stimulation of STAT3 signaling pathway. Our study not only clarified the role of STAT3 signaling pathway in oxidative stress-induced neuronal cell death, but also identified its involvement in the protection mechanism of EGCG on neurons in PD. The data resulting from our study also suggest that STAT3 may serve as a potential therapeutic target for the drug development in PD.

Pages 305-318
Kristyn A. Bates, Hamid R. Sohrabi, Mark Rodrigues, John Beilby, Satvinder S. Dhaliwal, Kevin Taddei, Arthur Criddle, Megan Wraith, Matthew Howard, Georgia Martins, Athena Paton, Pankaj Mehta, Jonathan K. Foster, Ian J. Martins, Nicola T. Lautenschlager, Frank L. Mastaglia, Simon M. Laws, Samuel E. Gandy, Ralph N. Martins
Association of Cardiovascular Factors and Alzheimer’s Disease Plasma Amyloid-β Protein in Subjective Memory Complainers
Abstract: A strong link is indicated between cardiovascular disease (CVD) and risk for developing Alzheimer’s disease (AD), which may be exacerbated by the major AD genetic risk factor apolipoprotein Ee4 (APOEε4). Since subjective memory complaint (SMC) may potentially be an early indicator for cognitive decline, we examined CVD risk factors in a cohort of SMC. As amyloid-β (Aβ) is considered to play a central role in AD, we hypothesized that the CVD risk profile (increased LDL, reduced HDL, and increased body fat) would be associated with plasma Aβ levels. We explored this in 198 individuals with and without SMC (average age=63 years). Correlations between Aβ40 and HDL were observed, which were stronger in non-APOEε4 carriers (rho=-0.315, p<0.001) and in SMC (rho=-0.322, p=0.01). There was no relationship between percentage body fat and Aβ40 in this cohort. Age and HDL remained predictive for plasma Aβ40 using multivariate regression analysis. We report a novel negative association between HDL and Aβ, which if demonstrated to be causal has implications for the development of lifestyle interventions and/or novel therapeutics. The relationship between HDL and Aβ and the potential significance of such an association needs to be validated in a larger longitudinal study.

Pages 319-325
Elena Tortosa, Ismael Santa-Maria, Francisco Moreno, Filip Lim, Mar Perez, Jesús Avila
Binding of Hsp90 to Tau Promotes a Conformational Change and Aggregation of Tau Protein
Abstract: Tau pathology, associated with Alzheimer’s disease, is characterized by the presence of phosphorylated and aggregated tau. Phosphorylation of tau takes place mainly in the vicinity of the tubulin-binding region of the molecule and its self aggregation is also mediated via this tubulin-binding region. Tau phosphorylation and aggregation have been related with conformational changes of the protein. These changes could be regulated by chaperones such as heat shock proteins, since one of these, heat shock protein 90 (Hsp90), has already been described as a putative tau-binding protein. In this work, we have confirmed the interaction of Hsp90 with tau protein and report that binding of Hsp90 to tau facilitates a conformational change that could result in its phosphorylation by glycogen synthase kinase 3 and its aggregation into filamentous structures.

Pages 327-336
Amalia M. Dolga, Ivica Granic, Ingrid M. Nijholt, Csaba Nyakas, Eddy A. van der Zee, Paul G.M. Luiten, Ulrich L.M. Eisel (Communicated by Angelika Bierhaus)
Pretreatment with Lovastatin Prevents N-Methyl-D-Aspartate-Induced Neurodegeneration in the Magnocellular Nucleus Basalis and Behavioral Dysfunction
Abstract: Besides a beneficial cardiovascular effect, it was recently suggested that statins can also exert neuroprotective actions. In a previous study, we provided in vitro evidence that lovastatin treatment abates excitotoxic cell death in primary cortical neurons. Here, we investigated the neuroprotective effect of lovastatin in an in vivo mouse model. We found that administration of lovastatin (20 mg/kg) significantly protects cholinergic neurons and their cortical projections against N-methyl-D-aspartate (60 nmol)-induced cell death in the magnocellular nucleus basalis, a neuronal cell group that is characteristically affected in Alzheimer’s disease. Furthermore, lovastatin-mediated neuroprotection was shown to be dependent on protein kinase B (PKB)/Akt signaling since treatment with the PKB/Akt inhibitor LY294002 blocked the lovastatin-induced neuroprotective effect. The loss of cholinergic neurons after the lesion in the magnocellular nucleus basalis resulted in memory impairment as tested in a passive avoidance paradigm. This was reverted by pre-lesion lovastatin treatment. From these studies we conclude that treatment with lovastatin may provide protection against neuronal injury in excitotoxic conditions associated with neurodegenerative diseases including Alzheimer’s disease.

Pages 337-341
Sid E. O’Bryant, Valerie Hobson, James R. Hall, Stephen C. Waring, Wenyan Chan, Paul Massman, Laura Lacritz, C. Munro Cullum, Ramon Diaz-Arrastia; for the Texas Alzheimer’s Research Consortium (Communciated by Marwan Sabbagh)
Brain-Derived Neurotrophic Factor Levels in Alzheimer’s Disease
Abstract: The current search for biomarkers that are diagnostic and/or prognostic of Alzheimer’s disease (AD) is of vital importance given the rapidly aging population. It was recently reported that brain-derived neurotrophic factor (BDNF) fluctuated according to AD severity, suggesting that BDNF might have utility for diagnostics and monitoring of therapeutic efficacy. The current study sought to examine whether BDNF levels varied according to AD severity, as previously reported. There were 196 participants (Probable AD, n = 98; Controls, n = 98) in the Texas Alzheimer’s Research Consortium (TARC) Longitudinal Research Cohort available for analysis. BDNF levels were assayed via multiplex immunoassay. Regression analyses were utilized to examine the relation between BDNF levels, Mini-Mental Status Examination, and Clinical Dementia Rating scores adjusting for age and gender. In adjusted models, BDNF levels did not distinguish between AD patients and normal controls and did not significantly predict AD severity or global cognitive functioning. In conclusion, these findings do not support the notion that BDNF serves as a diagnostic marker for AD or disease severity. It is likely that the most accurate approach to identifying biomarkers of AD will be through an algorithmic approach that combines multiple markers reflective of various pathways.

Pages 343-348
Fereshteh Sedaghat, Eleni Dedousi, Vasiliki Costa, Athanasios S. Dimitriadis, Stavros J. Baloyannis (Communicated by Kurt Jellinger)
Plasma Level of Amyloid β1-42 Is Independent of Neuronal Function in Alzheimer’s Disease
Abstract: The aggregation of amyloid-β42 (Aβ42) constitutes one of the major pathogenic events in Alzheimer’s disease (AD), and the study of regional cerebral blood flow (rCBF), using single photon emission computed tomography (SPECT), aids the diagnosis of AD. In this study, we evaluated whether there was a correlation between rCBF in brain regions and plasma levels of Aβ1-42 in AD. 29 patients (mean age 71 ± 9) with a diagnosis of AD who fulfilled NINCDS-ADRDA criteria with a mean Mini-Mental Status Examination score of 15 ± 9 and 16 normal controls (mean age 64 ± 8) underwent SPECT brain imaging with hexamethylpropylene amine oxime, and semiquantitative analysis of rCBF was performed. Plasma samples were collected the same day of the SPECT and plasma Aβ1-42 measured by ELISA. A significant reduction of rCBF was observed in most regions in AD compared to controls, whereas mean plasma Aβ42 did not differ between the two groups. There was no correlation between rCBF in any region and plasma Aβ42 nor any correlations between gender, age, and severity with plasma levels of Aβ42. Since rCBF is coupled to neuronal activity, we conclude that plasma Aβ1-42 concentration is independent of neuronal function in every single region of the brain.

Pages 349-357
Vito Davide Moretti, Michela Pievani, Claudia Fracassi, Giuliano Binetti, Sandra Rosini, Cristina Geroldi, Orazio Zanetti, Paolo M. Rossini, Giovanni B. Frisoni
Increase of Theta/Gamma and Alpha3/Alpha2 Ratio is Associated with Amygdalo-Hippocampal Complex Atrophy
Abstract: We evaluated the association between amygdalo-hippocampal complex (AHC) atrophy and two electroencephalography (EEG) markers of cognitive decline: increase of theta/gamma and increase of alpha3/alpha2 relative power ratio. Seventy-nine subjects with mild cognitive impairment (MCI) underwent EEG recording and magnetic resonance imaging scan. Based on the tertiles values of decreasing AHC volume, three groups of AHC growing atrophy were obtained. The groups were characterized by the performance to cognitive tests and theta/gamma and alpha3/alpha2 relative power ratio. AHC atrophy is associated with memory deficits as well as with increase of theta/gamma and alpha3/alpha2 ratio. Moreover, when the amygdalar and hippocampal volume are separately considered within AHC, the increase of theta/gamma ratio is best associated with amygdalar atrophy whereas alpha3/alpha2 ratio is best associated with hippocampal atrophy. AHC atrophy is associated with memory deficits and EEG markers of cognitive decline. So far, these EEG markers could have a prospective value in differential diagnosis between patients with MCI who develop dementia and those who do not as well as between MCI patients who will develop Alzheimer’s disease and those who develop non-Alzheimer’s disease dementias. The alterations of the functional connections, inducing global network pathological changes, in the whole AHC could better explain MCI state.

Pages 359-368
Ewa Golanska, Krystyna Hulas-Bigoszewska, Monika Sieruta, Izabela Zawlik, Monika Witusik, Sylwia M. Gresner, Tomasz Sobow, Maria Styczynska, Beata Peplonska, Maria Barcikowska, Pawel P. Liberski, Elizabeth H. Corder (Communicated by Eliecer Coto)
Earlier Onset of Alzheimer’s Disease: Risk Polymorphisms Within PRNP, PRND, CYP46, and APOE Genes
Abstract: We studied eight polymorphisms within APOE, PRNP, PRND,and CYP46 genes in 213 Polish late-onset patients with Alzheimer’s disease (AD) and 171 non-demented elderly controls. A latent classification approach, grade-of-membership analysis, was taken to identify three extreme pure type risk sets defined by the probabilities of being affected with AD and for genotypes found at the examined genes. Sets I and II represented high intrinsic risk, having a higher density of various genotypes compared to set III, at low intrinsic risk. A gradient of onset age depending on membership in the risk sets was also observed. Logistic regression analysis showed that the highest risk for AD was found for individuals who co-inherited APOE ε4 allele, PRNP codon 129 homozygosity, PRND codon 174 Thr allele, and CYP46 rs754203 g allele. AD can be influenced by genetic profiles leading to appearance of the disease, composed of genes which separately evoke a little or unnoticeable effect. Moreover, there may be multiple sufficient risk sets for AD. Looking at multiple genes together rather than analyzing them individually, may improve identification of risk alleles.

Pages 369-382
Mireille Basselin, Henry N. Nguyen, Lisa Chang, Jane M. Bell, Stanley I. Rapoport (Communicated by Marwan Sabbagh)
Acute but not Chronic Donepezil Administration Increases Muscarinic Receptor-Mediated Brain Signaling Involving Arachidonic Acid in Unanesthetized Rats
Abstract: Donepezil, an acetylcholinesterase (AChE) inhibitor used for treating Alzheimer’s disease patients, is thought to act by increasing brain extracellular acetylcholine (ACh), and ACh binding to cholinergic receptors. Muscarinic receptors are coupled to cytosolic phospholipase A2 (cPLA2) activation and arachidonic acid (AA) release from synaptic membrane phospholipid. This activation can be imaged in rodents as an AA incorporation coefficient k*, using quantitative autoradiography. Acute and chronic effects of donepezil on the AA signal, k* for AA, were measured in 81 brain regions of unanesthetized rats. Twenty min after a single oral dose (3.0 mg/kg) of donepezil, k* was increased significantly in 37 brain regions, whereas k* did not differ from control 7 h afterwards or following chronic (21 days) of donepezil. Pretreatment with atropine prevented the 20-min increments in k* following donepezil. Donepezil also increased the brain ACh concentration and reduced brain AChE activity, but did not change cPLA2 activity, regardless of administration regimen. These results show that donepezil acutely increases the brain AA signal that is mediated by ACh acting at muscarinic receptors, but that this signal is rapidly desensitized despite continued elevated brain ACh concentration. In contrast, the AA signal in response to arecoline was not altered following donepezil.

Pages 393-389
Livia Bernardi, Silvana Geracitano, Rosanna Colao, Gianfranco Puccio, Maura Gallo, Maria Anfossi, Francesca Frangipane, Sabrina A.M. Curcio, Maria Mirabelli, Carmine Tomaino, Franca Vasso, Nicoletta Smirne, Raffaele Maletta, Amalia C. Bruni (Communicated by Patrizia Mecocci)
AβPP A713T Mutation in Late Onset Alzheimer’s Disease with Cerebrovascular Lesions
Abstract: Mutations in the amyloid-β protein precursor (AβPP) gene can cause autosomal dominant early-onset Alzheimer’s disease, Alzheimer’s disease (AD) associated with cerebral amyloid angiopathy (CAA), cerebral hemorrhage, or both defining AD-AβPP related as a complex disease. We have previously reported that the AβPP A713T mutation is associated with AD and subcortical ischemic lesions at magnetic resonance imaging in a large family in which neuropathology evidenced CAA, stroke, and AD lesions. The objective of this clinical and molecular study was to investigate AβPP gene mutations in 59 patients affected by AD with cerebrovascular lesions (CVLs) and a family history of dementia. We identified three affected subjects with the AβPP A713T mutation. Since the prevalence of this mutation worldwide is very low, this suggests that a common founder could exist in southern Italy. The pathogenicity of this mutation was confirmed and the clinical AD phenotype with CVLs seems to be a distinctive feature at least in the southern Italian population. The identification of these patients suggests that genetic epidemiology in large cohorts of familial late onset AD with CVLs would increase the probability of identifying AβPP mutations still underestimated.

Pages 391-397
David H. Burns, Scott Rosendahl, Dirk Bandilla, Olivier C. Maes, Howard M. Chertkow, Hyman M. Schipper (Communicated by Othman Ghribi)
Near-Infrared Spectroscopy of Blood Plasma for Diagnosis of Sporadic Alzheimer’s Disease
Abstract: There are currently no accepted blood-based biomarkers of sporadic Alzheimer’s disease (AD). Augmented oxidative stress has been implicated in both neural and peripheral AD tissues. In this study, we determined whether short-wavelength near-infrared (NIR) spectrophotometry of blood plasma differentiates mild sporadic AD from normal aging. NIR analysis was conducted on 75 µl plasma samples from 19 AD, 27 amnestic MCI, and 17 normal elderly control (NEC) persons using an optical fiber-coupled, holographic grating-based NIR spectrograph. Five spectral bands associated with heme, R-CH, R-OH, H2O, and R-NH functional groups, were sensitive to oxidative modification in pre-clinical studies and were pre-selected to develop a logistic regression model for sample classification. This model differentiated AD from NEC samples with a sensitivity of 80% and specificity of 77%. Fifteen and twelve MCI patients were classified with the NEC and AD groups, respectively. The spectra were not influenced by age, gender, exposure to cholinesterase inhibitors or vitamin E, or sample storage time. The NIR data further implicate oxidative stress in the systemic pathophysiology of sporadic AD and differentiate mild (and possibly pre-clinical) AD from NEC individuals with moderate-high accuracy. The procedure is minimally-invasive, rapid, relatively-inexpensive, and may provide a useful biological marker of sporadic AD.

Pages 399-407
Renate R. Zilkens, Katrina Spilsbury, David G. Bruce, James B. Semmens
Clinical Epidemiology and In-Patient Hospital Use in the Last Year of Life (1990-2005) of 29,884 Western Australians with Dementia
Abstract: Dementia-related healthcare planning requires accurate information on dementia patient characteristics and hospitalization trends at a population level. This population-based retrospective cohort study was designed to evaluate factors associated with total hospital length-of-stay (tLOS) in the last year of life (1990-2005) in Western Australians with dementia. Using linked hospital and death records, 29,884 dementia cases were identified. The average tLOS in the last year of life for all cases was 31.8 days. tLOS was longer for vascular dementia than Alzheimer’s disease (41 versus 28 days; Rate Ratio (RR) 1.4; 95% CI 1.3-1.6). After multivariate adjustment, tLOS was longer for males than females (RR 1.4; 95% CI 1.3-1.4); longer for remote (RR 1.7; 95% CI 1.4-2.0) and very remote (RR3.0; 95% CI 2.4-3.9) compared to metropolitan areas; and shorter with increasing age. 62% of admissions were emergency admissions. “Problems accessing alternative medical facilities” and “problems related to care provider dependency” accounted for a total of 16.4% of all bed days. In conclusion, people with dementia spend a considerable period of time in the hospital during their last year of life. Consideration of geographic isolation and accessibility to non-hospital facilities in dementia-related healthcare planning may liberate in-patient beds for more elective and acute care admissions.

Pages 409-422
Zheng Jing, John Caltagarone, Robert Bowser
Altered Subcellular Distribution of c-Abl in Alzheimer’s Disease
Abstract: c-Abl is a non-receptor tyrosine kinase that participates in multiple signaling pathways linking the cell surface, cytoskeleton, and the nucleus. Recent in vitro studies have also linked c-Abl to amyloid-β-induced toxicity and tau phosphorylation. To further characterize a potential role of c-Abl in Alzheimer’s disease (AD), we examined the expression and distribution of total and phosphorylated forms of c-Abl in the hippocampus of AD and control subjects. Laser scanning confocal microscopy was used to examine the colocalization of c-Abl with AD pathology. Our results demonstrate alterations in the presence and distribution of c-Abl and phosphorylated isoforms of c-Abl within the hippocampus during AD. Total unphosphorylated c-Abl was highest in non-demented control hippocampus. Activated isoforms of c-Abl were most abundant in AD hippocampus and co-localized with AD pathology, including granulovacuolar degeneration bodies. c-Abl interacts with phosphorylated tau in AD brain and may contribute to the formation of tau pathology. These studies demonstrate altered activation and distribution of c-Abl during AD, suggesting a role for c-Abl in Ab signal transduction and generation of tau pathology in AD.

Pages 423-440
Cristina Grossi, Simona Francese, Angela Casini, Maria Cristina Rosi, Ilaria Luccarini, Anna Fiorentini, Chiara Gabbiani, Luigi Messori, Gloriano Moneti, Fiorella Casamenti (Communicated by Juha Rinne)
Clioquinol Decreases Amyloid-β Burden and Reduces Working Memory Impairment in a Transgenic Mouse Model of Alzheimer’s Disease
Abstract: Clioquinol (CQ) is a “metal protein attenuating compound” that crosses the blood-brain barrier and binds, with high affinity, copper(II) and zinc(II), two metal ions critically involved in amyloid-β aggregation and toxicity. CQ was recently proposed for the treatment of Alzheimer’s disease, but controversial data have been reported so far concerning its real therapeutic advantages. We describe here results of chronic CQ treatment in the TgCRND8 mouse model of Alzheimer’s disease. Remarkably, based on classical behavioral tests, CQ treatment was found to revert, to a large extent, the working memory impairments that are characteristic of this mouse model. Pairwise, a significant reduction of amyloid-β plaque burden, both in the cortex and in the hippocampus, was detected as well as an attenuation of astrogliosis. MALDI Mass Spectrometry Imaging technique revealed a specific localization of CQ in the above mentioned brain areas. Modest but significant effects on the absolute and relative brain concentrations of the three most important biometals (i.e., copper, zinc, and iron) were highlighted following CQ treatment. The pharmacological and mechanistic implications of the above findings are thoroughly discussed.

Pages 441-448
Noriko Sato, Akinori Ueki, Hideo Ueno, Hidetaka Shinjo, Yoshio Morita
Dopamine D3 Receptor Gene Polymorphism Influences on Behavioral and Psychological Symptoms of Dementia (BPSD) in Mild Dementia of Alzheimer’s Type
Abstract: Dopamine D3 receptor (DRD3) is present in the limbic system, which is thought to regulate affect, cognition, and activity. Thus a functional change in the DRD3 gene could in turn affect the cognitive and psychiatric symptoms of dementia of Alzheimer’s type (DAT). We investigated a possible association of DRD3 genotype with DAT and the behavioral and psychological symptoms of dementia (BPSD) in mild DAT. The genotyping for DRD3 and apolipoprotein E (ApoE) was determined using restriction fragment length polymorphism in 210 patients with mild DAT and 224 age- and sex-matched non-demented controls. The occurrence of BPSD during the course of mild dementia was demonstrated using the Behavioral Pathology in Alzheimer’s Disease rating scale (BEHAVE-AD). No significant differences in DRD3 genotype were identified between DAT and controls, regardless of ApoE ε4. Among the DAT with BPSD, however, a significant association was observed between the presence of the DRD3 glycine allele and paranoid and delusional ideation, regardless of ApoE ε4. In conclusion, DRD3 gene polymorphism is unlikely to play a substantial role in conferring susceptibility to DAT, but it may be involved in the development of paranoid and delusional ideation during the course of mild DAT.

Pages 449-452
Transcript of Live Discussion held at the Alzheimer Research Forum
Alzheimer Research Forum Live Discussion: Can We (Should We?) Develop “Smart Drugs” to Stave Off Age-Related Memory Loss?

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