Volume 32, Number 2, October 2012

Pages 243-266
Review
Gary W. Arendash
Transcranial Electromagnetic Treatment against Alzheimer’s Disease: Why it has the Potential to Trump Alzheimer’s Disease Drug Development
Abstract: The universal failure of pharmacologic interventions against Alzheimer’s disease (AD) appears largely due to their inability to get into neurons and the fact that most have a single mechanism-of-action. A non-invasive, neuromodulatory approach against AD has consequently emerged: transcranial electromagnetic treatment (TEMT). In AD transgenic mice, long-term TEMT prevents and reverses both cognitive impairment and brain amyloid-β (Aβ) deposition, while TEMT even improves cognitive performance in normal mice. Three disease-modifying and inter-related mechanisms of TEMT action have been identified in the brain: 1) anti-Aβ aggregation, both intraneuronally and extracellularly, 2) mitochondrial enhancement, and 3) increased neuronal activity. Long-term TEMT appears safe in that it does not impact brain temperature or oxidative stress levels, nor does it induce any abnormal histologic/anatomic changes in the brain or peripheral tissues. Future TEMT development in both AD mice and normal mice should involve head-only treatment to discover the most efficacious set of parameters for achieving faster and even greater cognitive benefit. Given the already extensive animal work completed, translational development of TEMT could occur relatively quickly to “proof of concept” AD clinical trials. TEMT’s mechanisms of action provide extraordinary therapeutic potential against other neurologic disorders/injuries, such as Parkinson’s disease, traumatic brain injury, and stroke.

Pages 267-272
Short Communication
M. Teresa Girão da Cruz, Jessica Jordão, Kevin A. DaSilva, Carlos A. Ayala-Grosso, Athéna Ypsilanti, Ying-Qi Weng, Frank M. LaFerla, JoAnne McLaurin, Isabelle Aubert (Handling Associate Editor: Elliott Mufson)
Early Increases in Soluble Amyloid-β Levels Coincide with Cholinergic Degeneration in 3xTg-AD mice
Abstract: Accumulation of amyloid-β peptides (Aβ) and cholinergic degeneration are hallmarks of Alzheimer’s disease (AD). In a triple transgenic mouse model of AD (3xTg-AD), soluble Aβ42 levels were detected in the septum by 2 months of age, reaching their highest levels at 3-6 months and decreasing at 12 months. Deficits in the number of septal cholinergic neurons and the length of hippocampal cholinergic axons were observed starting at 4 months in 3xTg-AD mice. Our results show that septal Aβ and septohippocampal cholinergic pathology in 3xTg-AD mice occur at an early stage of disease.

Supplementary Data for Girão da Cruz et al. article (PDF)

Pages 273-276
Short Communication
Bob Olsson, Clas Malmeström, Hans Basun, Peter Annas, Kina Höglund, Lars Lannfelt, Niels Andreasen, Henrik Zetterberg, Kaj Blennow
Extreme Stability of Chitotriosidase in Cerebrospinal Flulid makes it a Suitable Marker for Microglial Activation in Clinical Trials Abstract: Microglia is thought to be important in Alzheimer’s disease. Therefore, our aim was to investigate the usefulness of the microglial marker chitotriosidase in clinical trials. Chitotriosidase was analyzed in cerebrospinal fluid from Alzheimer’s disease patients on acetylcholine esterase inhibitors (AChEI) and in cerebrospinal fluid from multiple sclerosis patients before and after natalizumab treatment. Chitotriosidase activity was extremely stable during treatment with the non-inflammatory drug AChEI. However, the immunomodulatory treatment with natalizumab led to lower chitotriosidase activity. Thus, chitotriosidase may be useful in clinical trials where microglia is targeted or as a safety biomarker in other trials where the brain is a bystander organ.

Pages 277-289
Fabio Di Domenico, Eugenio Barone, Cesare Mancuso, Marzia Perluigi, Annalisa Cocciolo, Patrizia Mecocci, D. Allan Butterfield, Raffaella Coccia (Handling Associate Editor: Kenneth Hensley)
HO-1/BVR-A System Analysis in Plasma from Probable Alzheimer’s Disease and Mild Cognitive Impairment Subjects: A Potential Biochemical Marker for the Prediction of the Disease
Abstract: Several studies showed increased oxidative and nitrosative stress in plasma from patients with Alzheimer’s disease (AD), however, little and controversial knowledge has emerged about the antioxidant functionality of the heme oxygenase-1/biliverdin reductase-A (HO-1/BVR-A) system in blood. The current study reports increased levels of both HO-1 and BVR-A in plasma from probable AD patients, as a result of the increased oxidative environment. However, the increase of oxidative stress in plasma result also in the increase of BVR-A 3-nitrotyrosine levels and the decrease of BVR-A phosphotyrosine levels and reductase activity, suggesting that nitrosative stress play the prominent oxidative role in plasma during AD. Our data on HO-1/BVR-A status in plasma closely correlate with recent reports in hippocampus of subjects with AD and arguably its early form, mild cognitive impairment. Moreover, we show that alterations on HO-1/BVR-A system are tightly connected with cognitive decline indexed by Mini-Mental Status Exam scores. We hypothesize that the HO-1/BVR-A system status in plasma might reflect the ongoing situation in the brain, offering an important biochemical tool for the potential prediction of AD at the earliest stages of the disease.

Supplementary Data for Di Domenico et al. article (PDF)

Pages 291-305
Claudine L. Bitel, Chinnaswamy Kasinathan, Rajesh H. Kaswala, William L Klein, Peter H. Frederikse
Amyloid-β and Tau Pathology of Alzheimer’s Disease Induced by Diabetes in an Animal Model
Abstract: Alzheimer’s disease (AD) is the major age-dependent disease of the brain, but what instigates late-onset AD is not yet clear. Epidemiological, animal model, and cell biology findings suggest links between AD and diabetes. Although AD pathology is accelerated by diabetes in mice engineered to accumulate human-sequence amyloid-β (Aβ) peptides, they do not adequately model non-inherited AD. We investigated AD-type pathology induced solely by diabetes in genetically unmodified rabbits which generate human-sequence Aβ peptides. After 15 weeks, alloxan-treated diabetic rabbits with expected high blood glucose showed ~5-fold increase in Aβ40/Aβ42 in cortex and hippocampus, and significantly, generated Aβ-derived assemblies found in human AD. Deposits of these putative pathogenic toxins were detected by Aβ/Aβ oligomer antibodies in brain parenchyma and surrounding vasculature, also co-localizing with markedly elevated levels of RAGE. Soluble brain extracts showed diabetes-induced buildup of Aβ oligomers on dot-blots. Phospho-tau also was clearly elevated, overlapping with βIII-tubulin along neuronal tracts. Indications of retina involvement in AD led to examination of AD-type pathology in diabetic retinas and showed Aβ accumulation in ganglion and inner nuclear cell layers using Aβ/oligomer antibodies, and RAGE again was elevated. Our study identifies emergence of AD pathology in brain and retina as a major consequence of diabetes; implicating dysfunctional insulin signaling in late-onset AD, and a potential relationship between Aβ -derived neurotoxins and retinal degeneration in aging and diabetes, as well as AD. AD-type pathology demonstrated in genetically unmodified rabbits calls attention to the considerable potential of the model for investigations of AD pathogenesis, diagnostics, and therapeutics.

Pages 307-316
Marcos Antonio Lopes, Eduardo Ferrioli, Eduardo Yoshio Nakano, Júlio Litvoc, Cássio Machado Campos Bottino (Handling Associate Editor: Carol Brayne)
High Prevalence of Dementia in a Community-Based Survey of Older People from Brazil: Association with Intellectual Activity rather than Education
Abstract: Although several surveys have been conducted around the world, few surveys have investigated the prevalence of dementia in Latin America. The aim of this study was to estimate dementia prevalence in a community sample in Ribeirão Preto, Brazil, and to evaluate its distribution across several socio-demographic and clinical characteristics and habits. The population was aged 60 years and older and a representative sample from three different social regions. The screening instruments used in the first phase were the Mini-Mental State Examination, the Fuld Object-Memory Evaluation, the Informant Questionnaire on Cognitive Decline in the Elderly, and the Bayer Activities of Daily Living Scale. In the second phase, the Cambridge Examination was employed to diagnose dementia according to the DSM-IV criteria. The estimate of dementia prevalence was adjusted for screening instrument performance, using the positive and negative predictive values. The data were weighted to compare frequencies, considering the sampling and the non-response effect, and subjected to multivariate analysis. In all, 1.145 elderly subjects were evaluated (mean age: 70.9 years), of whom 63.4% were female and 52.8% had up to 4 years of schooling (participation rates at the first and the second phases were 62.6 and 60%, respectively). The observed and estimated prevalences of dementia were 5.9% and 12.5%, respectively (n=68). Alzheimer’s disease was the main cause (60.3%). Dementia was associated with old age, low education, stroke, absence of arthritis, and not reading books. The estimated prevalence of dementia was higher than the prevalence previously found. Associated factors confirmed the importance of intellectual activities in prevention.

Pages 317-328
Jinglong Wu, Jiajia Yang, Yinghua Yu, Qi Li, Naoya Nakamura, Yong Shen, Yasuyuki Ohta, Shengyuan Yu, Koji Abe (Handling Associate Editor: Jin-Jing Pei)
Delayed Audiovisual Integration of Patients with Mild Cognitive Impairment and Alzheimer’s Disease Compared with Normal Aged Controls
Abstract: The human brain can anatomically combine task-relevant information from different sensory pathways to form a unified perception; this process is called multisensory integration. The aim of the present study was to test whether the multisensory integration abilities of patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) differed from those of normal aged controls (NC). A total of 64 subjects were divided into three groups: NC individuals (n = 24), MCI patients (n = 19), and probable AD patients (n = 21). All of the subjects were asked to perform three separate audiovisual integration tasks and were instructed to press the response key associated with the auditory, visual, or audiovisual stimuli in the three tasks. The accuracy and response time (RT) of each task were measured, and the RTs were analyzed using cumulative distribution functions to observe the audiovisual integration. Our results suggest that the mean RT of patients with AD was significantly longer than those of patients with MCI and NC individuals. Interestingly, we found that patients with both MCI and AD exhibited adequate audiovisual integration, and a greater peak (time bin with the highest percentage of benefit) and broader temporal window (time duration of benefit) of multisensory enhancement were observed. However, the onset time and peak benefit of audiovisual integration in MCI and AD patients occurred significantly later than did those of the NC. This finding indicates that the cognitive functional deficits of patients with MCI and AD contribute to the differences in performance enhancements of audiovisual integration compared with NC.

Pages 329-339
Rosebud O. Roberts, Lewis A. Roberts, Yonas E. Geda, Ruth H. Cha, V. Shane Pankratz, Helen M. O’Connor, David S. Knopman, Ronald C. Petersen (Handling Associate Editor: Francesco Panza)
Relative Intake of Macronutrients Impacts Risk of Mild Cognitive Impairment or Dementia
Abstract: High caloric intake has been associated with an increased risk of cognitive impairment. Total caloric intake is determined by the calories derived from macronutrients. The objective of the study was to investigate the association between percent of daily energy (calories) from macronutrients and incident mild cognitive impairment (MCI) or dementia. Participants were a population-based prospective cohort of elderly persons who were followed over a median 3.7 years (interquartile range, 2.5-3.9) of follow-up. At baseline and every 15 months, participants (median age, 79.5 years) were evaluated using the Clinical Dementia Rating scale, a neurological evaluation, and neuropsychological testing for a diagnosis of MCI, normal cognition, or dementia. Participants also completed a 128-item food-frequency questionnaire at baseline; total daily caloric and macronutrient intakes were calculated using an established database. The percent of total daily energy from protein (% protein), carbohydrate (% carbohydrate), and total fat (% fat) was computed. Among 937 subjects who were cognitively normal at baseline, 200 developed incident MCI or dementia. The risk of MCI or dementia (hazard ratio, [95% confidence interval]) was elevated in subjects with high % carbohydrate (upper quartile: 1.89 [1.17-3.06]; p for trend=0.004), but was reduced in subjects with high % fat (upper quartile: 0.56 [0.34-0.91]; p for trend=0.03), and high % protein (upper quartile 0.79 [0.52 - 1.20]; p for trend=0.03) in the fully adjusted models. A dietary pattern with relatively high caloric intake from carbohydrates and low caloric intake from fat and proteins may increase the risk of MCI or dementia in elderly persons.

Pages 341-355
Silvia Maioli, Elena Puerta, Paula Merino-Serrais, Laura Fusari, Francisco Gil-Bea, Roberto Rimondini, Angel Cedazo-Minguez
Combination of Apolipoprotein E4 and High Carbohydrate Diet Reduces Hippocampal BDNF and Arc Levels and Impairs Memory in Young Mice
Abstract: The presence of the E4 allele of apolipoprotein E (apoE) is the strongest known genetic risk factor for sporadic Alzheimer’s disease (AD). Other risk factors for developing AD have been identified, including lifestyle such as dietary habits. The present study was designed to explore the impact of the interaction between variant human apoE isoforms and a high carbohydrate diet (HCD) on mechanisms behind learning and memory retention. As an investigative model, we compared young apoE3 and apoE4 target replacement mice fed on a HCD for 6 months. Our results indicate that HCD compromises memory processes in apoE4 mice. ApoE4 mice on HCD showed decreased activity-regulated cytoskeletal-associated protein (Arc) and brain derived neurotrophic factor (BDNF) levels, as well as decreased BDNF signaling in the hippocampus. In contrast, apoE3 mice were resistant to the deleterious effects of HCD on both behavior and memory-related proteins. Our results support the hypothesis that already in mid-life, genetic, and environmental risk factors act together on the mechanisms behind cognitive impairment.

Pages 357-372
Gregory J. Tranah, Michael A. Nalls, Shana M. Katzman, Jennifer S. Yokoyama, Ernest T. Lam, Yiqiang Zhao, Sean Mooney, Fridtjof Thomas, Anne B. Newman, Yongmei Liu, Steven R. Cummings, Tamara B. Harris, Kristine Yaffe for the Health, Aging and Body Composition Study (Handling Associate Editor: Aleksandra Maruszak)
Mitochondrial DNA Sequence Variation Associated with Dementia and Cognitive Function in the Elderly
Abstract: Mitochondrial dysfunction is a prominent hallmark of Alzheimer’s disease (AD). Mitochondrial DNA (mtDNA) damage may be a major cause of abnormal reactive oxidative species production in AD or increase neuronal susceptibility to oxidative injury during aging. The purpose of this study was to assess the influence of mtDNA sequence variation on clinically significant cognitive impairment and dementia risk in the population-based Health, Aging, and Body Composition (Health ABC) Study. We first investigated the role of common mtDNA haplogroups and individual variants on dementia risk and 8-year change on the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) among 1,631 participants of European genetic ancestry. Participants were free of dementia at baseline and incidence was determined in 273 cases from hospital and medication records over 10-12 follow-up years. Participants from haplogroup T had a statistically significant increased risk of developing dementia (OR=1.86, 95%CI=1.23,2.82, p=0.0008) and haplogroup J participants experienced a statistically significant 8-year decline in 3MS (β=-0.14, 95%CI =-0.27,-0.03, p=0.0006), both compared with common haplogroup H. The m.15244A>G, p.G166G, CytB variant was associated with a significant decline in DSST score (β=-0.58, 95%CI -0.89,-0.28, p=0.00019) and the m.14178T>C, p.I166V, ND6 variant was associated with a significant decline in 3MS score (β=-0.87, 95%CI -1.31,-3.86, p=0.00012). Finally, we sequenced the complete ~16.5kb mtDNA from 135 Health ABC participants and identified several highly conserved and potentially functional nonsynonymous variants unique to 22 dementia cases and aggregate sequence variation across the hypervariable 2-3 regions that influences 3MS and DSST scores.

Supplementary Data for Tranah et al. article (PDF)

Pages 373-385
Peng Yu, Robert A. Dean, Stephen D. Hall, Yuan Qi, Gopalan Sethuraman, Brian A. Willis, Eric R. Siemers, Ferenc Martenyi, Johannes T. Tauscher, Adam J. Schwarz; for the Alzheimer’s Disease Neuroimaging Intiative
Enriching Amnestic Mild Cognitive Impairment Populations for Clinical Trials: Optimal Combination of Biomarkers to Predict Conversion to Dementia
Abstract: The goal of this study was to identify the optimal combination of magnetic resonance imaging (MRI), [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET), and cerebrospinal fluid (CSF) biomarkers to predict conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer’s disease (AD) dementia within two years, for enriching clinical trial populations. Data from 63 subjects in the Alzheimer’s Disease Neuroimaging Initiative aMCI cohort who had MRI and FDG-PET imaging along with CSF data at baseline and at least two years clinical follow-up were used. A Bayesian classification method was used to determine which combination of 31 variables (MRI, FDG-PET, CSF measurements, apolipoprotein E (ApoE) genotype, and cognitive scores) provided the most accurate prediction of aMCI to AD conversion. The cost and time trade-offs for the use of these biomarkers as inclusion criteria in clinical trials were evaluated. Using the combination of all biomarkers, ApoE genotype, and cognitive scores, we achieved an accuracy of 81% in predicting aMCI to AD conversion. With only ApoE genotype and cognitive scores, the prediction accuracy decreased to 62%. By comparing individual modalities, we found that MRI measures had the best predictive power (accuracy=78%), followed by ApoE, FDG-PET, CSF, and the Alzheimer's disease assessment scale-cognitive subscale. The combination of biomarkers from different modalities, measuring complementary aspects of AD pathology, provided the most accurate prediction of aMCI to AD conversion within two years. This was predominantly driven by MRI measures, which emerged as the single most powerful modality. Overall, the combination of MRI, ApoE, and cognitive scores provided the best trade-off between cost and time compared with other biomarker combinations for patient recruitment in clinical trial.

Supplementary Data for Yu et al. article (PDF)

Pages 387-396
Feng Bai, Yongmei Shi, Yonggui Yuan, Chunxian Yue, Liying Zhuang, Xiaohui Xu, Xiaoyan Liu, Zhijun Zhang
Association of a GSK-3β Polymorphism with Brain Resting-State Function in Amnestic-Type Mild Cognitive Impairment
Abstract: The glycogen synthase kinase-3β (GSK-3β) gene has been implicated in Alzheimer's disease (AD). Polymorphisms in this gene are plausible modulators of brain function. However, little is known about the potential role of the GSK-3β rs334558 polymorphism, which has been associated with amnestic mild cognitive impairment (aMCI), which is itself associated with a high risk of AD. In this study, 43 aMCI patients and 30 healthy controls underwent resting-state functional magnetic resonance imaging, and their GSK-3β rs334558 genotypes were evaluated to determine the effect of the risk variant on regional brain activity and functional networks in these subjects. Then, gene-brain-behavior relationships were examined. Compared with the controls, aMCI subjects with the higher risk T allele had more deficits in regional activation of the right superior frontal gyrus (rSFG), while a higher functional connectivity of the rSFG was observed in TT/CT carriers. Further correlative analyses revealed that the increase in rSFG connectivity was robustly positively correlated with non-memory performance in aMCI GSK-3β rs334558 TT/CT carriers. Our findings are the first to show that a clinically significant proportion of resting-state brain function variation in aMCI patients may be explained by genetic variation at the GSK-3βrs334558 locus in ways that are distinguishable from controls.

Pages 397-415
Emilia Bialopiotrowicz, Aleksandra Szybinska, Bozena Kuzniewska, Laura Buizza, Daniela Uberti, Jacek Kuznicki, Urszula Wojda
Highly Pathogenic Alzheimer’s Disease Presenilin 1 P117R Mutation Causes a specific Increase in p53 and p21 Protein Levels and Cell Cycle Dysregulation in Human Lymphocytes
Abstract: Cell cycle (CC) reentry in neurons precedes the formation of amyloid-β (Aβ) plaques in Alzheimer’s disease (AD). CC alterations were also detected in lymphocytes from sporadic AD patients. In the present study, we investigated the influence of nine presenilin 1 (PS1) mutations (P117R, M139V, L153V, H163R, S170F, F177L, I213F, L226F, E318G) on CC and Aβ production in immortalized B-lymphocytes from familial AD (FAD) patients and in stably transfected human embryonic kidney cells. In both cell types, only the P117R mutation increased levels of key G1/S phase regulatory proteins, p53, and its effector p21, causing G1 phase prolongation with simultaneous S phase shortening, and lowering basal apoptosis. The CC changes were rescued by inhibition of p53, but not of γ-secretase. Moreover, the investigated PS1 mutants showed differences in the increased levels of secreted Aβ40 and Aβ42 and in Aβ42/Aβ40 ratios, but these differences did not correlate with CC patterns. Altogether, we found that both CC regulation and Aβ production differentiate PS1 mutations, and that CC PS1 activity is mediated by p53/p21 signaling but not by g-secretase activity. The identified CC dysregulation linked with increased p53 and p21 protein levels distinguishes the highly pathogenic PS1 P117R mutation and may contribute to the specific severity of the clinical progression of FAD associated with the mutation in the PS1 117 site. These findings suggest that impairment in lymphocyte CC might play a pathogenic function in AD and are relevant to the development of new diagnostic approaches and personalized therapeutic strategies.

Supplementary Data for Bialopiotrowicz et al. article (PDF)

Pages 417-429
Betsi Flores, Rommy von Bernhardi
Transforming Growth Factor β1 Modulates Amyloid β-Induced Glial Activation through the Smad3-Dependent Induction of MAPK Phosphatase-1
Abstract: Chronic neuroinflammation has been proposed as a driving force for Alzheimer's disease (AD), which is characterized by amyloid-β (Aβ) deposition, neurofibrillary tangles, neuronal loss, and activation of glial cells. Persistent activation of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) pathway has been reported, which induces an increased expression of inflammatory mediators. Transforming growth factor β1 (TGFβ1) is an inflammation modulator whose levels are increased in AD. However, its canonical signaling pathway, Smad, appears to be impaired. Our previous findings indicate that TGFβ1 plays a key role in the pathogenesis of neuroinflammation, but the molecular mechanisms underlying its effects are not completely elucidated. Here, we studied the potential role of MKP-1, a phosphatase that exerts negative regulation on MAPK signaling, in the modulatory actions of TGFβ1. Using rat primary glial cultures, we found that pretreatment with TGFβ1 for 48 h reduced the production of inflammatory mediators induced by Aβ42, a result that was associated with prevention of MAPK p38 activation, attenuation of NF-κB p65 nuclear translocation, and an increase in MKP-1 levels. Moreover, suppression of MKP-1 expression by siRNA and inhibition of Smad3 reversed the modulation of inflammatory response exerted by TGFβ1. These results indicate that TGFβ1 induces the expression of MKP-1 in glial cells through the Smad pathway and inhibits MAPK and NF-κB signaling, thus revealing a novel mechanism for the neuroprotective actions of TGFβ1. Further research would be important in order to characterize the role of this mechanism in the pathogenesis of AD.

Supplementary Data for Flores and von Bernhardi article (PDF)

Pages 431-436
Elizabeta B. Mukaetova-Ladinska, Zeinab Abdel-All, Joana Andrade, Richard J.Q. McNally, Peter W. James, Raj N. Kalaria, John T. O’Brien
Increase in Platelet Immunoglobulin in Alzheimer’s Disease is Lowered Following Cholinesterase Inhibitor Treatment: Preliminary Results
Abstract: We report a 16.5% increase in platelet immunoglobulin (Ig) content in subjects with Alzheimer’s disease (AD) in relation to cognitively intact individuals (p=0.021), whereas the plasma Ig levels were unaltered (p=0.428). The upregulation of platelet Ig was not explained by age, duration of dementia, or degree of cognitive impairment. However, AD subjects treated with cholinesterase inhibitors (n=21) had lower levels of platelet Ig (p=0.009) than AD subjects not treated with anti-dementia drugs (n=4) and similar to those of control subjects (n=24; p=0.069). The anti-dementia treatment did not influence the plasma Ig levels (p=0.177). These preliminary findings require further confirmation in studies on larger number of AD subjects with various stages of cognitive impairment, and who would be assessed prior to initiation of and during cholinesterase inhibitor treatment.

Pages 437-445
Gakuji Hashimoto, Mikako Sakurai, Andrew F. Teich, Faisal Saeed, Fahad Aziz, Ottavio Arancio (Handling Associate Editor: Luciano D’Adamio)
5-HT4 Receptor Stimulation Leads to Soluble AβPPα Production through MMP-9 Upregulation
Abstract: Serotonin 4 (5-HT4) receptor signaling does not only have the physiological function of improving cognition, but might also be helpful in the therapy of Alzheimer’s disease (AD) through regulation of the production of soluble amyloid-β protein precursor alpha (sAβPPα). To analyze the relationship between 5-HT4 receptor signaling and sAβPPα production, we stably transfected H4 cells with AβPP and 5-HT4 receptor (H4/AβPP/5-HT4 cells). We found that 24-h incubation with the 5-HT4 receptor agonist RS-67333 upregulates matrix metalloproteinase-9 (MMP-9). Furthermore, MMP-9 overexpression enhanced sAβPPα levels, whereas knockdown with MMP-9 siRNA decreased sAβPPα levels. When RS-67333 was injected for 10 days in Tg2576 mice, a model of amyloid-β peptide (Aβ) deposition, there was an increase in hippocampal levels of sAβPPα, C-terminal fragment α, and MMP-9, as well as a decrease in hippocampal senile plaque number and levels of the 40 amino acid peptide, Aβ40. Taken all together, these experiments demonstrate that 5-HT4 receptor stimulation induces expression of MMP-9 which cleaves AβPP through α-secretase-like activity, leading to an increase of sAβPPα levels and a reduction of Aβ load.

Pages 447-455
Susan A. Farr, Tulin O. Price, William A. Banks, Nuran Ercal, John E. Morley
Effect of Alpha-Lipoic Acid on Memory, Oxidation, and Lifespan in SAMP8 Mice
Abstract: Oxidative damage is associated with neurodegenerative disorders such as Alzheimer’s disease (AD). The antioxidant alpha-lipoic acid has been found to improve memory in mouse models of AD. Here, we administered alpha-lipoic acid daily to SAMP8 mice starting at 11 months of age and continuing until death. We found that treatment with alpha-lipoic acid decreased survival from 34 weeks in those receiving vehicle to 20 weeks. A subset of 18 month old mice given alpha-lipoic acid for two weeks and then tested in an object-place recognition paradigm had improved memory. A second subset of 18 month old mice given alpha-lipoic acid for two weeks and tested in the Barnes maze had improved learning. After testing, the mice were sacrificed and indices of oxidative damage were measured in the brain tissue. The mice that received alpha-lipoic acid had significantly increased glutathione and decreased glutathione peroxidase and malondialdehyde indicating reversal of oxidative stress. These results indicate that alpha-lipoic acid improves memory and reverses indices of oxidative stress in extremely old SAMP8 mice, but decreases lifespan. These findings are similar to studies using other types of antioxidants.

Pages 457-466
Andrea Tales, Ute Leonards, Aline Bompas, Robert J. Snowden, Michelle Philips, Gillian Porter, Judy Haworth, Gordon Wilcock, Antony Bayer (Handling Associate Editor: Kirk Daffner)
Intra-Individual Reaction Time Variability in Amnestic Mild Cognitive Impairment: A Precursor to Dementia?
Abstract: We used an exogenous target detection cueing paradigm to examine whether intra-individual reaction time variability (IIV) or phasic alerting varied significantly between patients with amnestic mild cognitive impairment (aMCI) (n =45) and healthy older adult controls (n = 31) or between those with aMCI who, within a 2.5 year follow-up period, developed dementia (n =13) and those who did not (n=26). Neither IIV, nor simple reaction time, differentiated aMCI from healthy aging, indicating that raised IIV and overall response slowing are not general characteristics of aMCI. However, within the aMCI group, IIV did differentiate between those who converted to dementia and those who remained with a diagnosis of aMCI (non-converters), being significantly more variable in those who later developed dementia. Furthermore, there was no difference in IIV between non-converters and healthy controls. High IIV appears related to an increased probability that an individual with aMCI will become demented within 2.5 years, rather than to amnestic dysfunction per se. In contrast, phasic alerting performance significantly differentiated aMCI from healthy aging, but failed to discriminate those with aMCI who developed dementia from those who did not. In addition, those patients with aMCI who did not develop dementia still showed a significantly poorer phasic alerting effect compared to healthy aging. The phasic alerting abnormality in aMCI compared to healthy aging does not appear specifically related to the performance of those patients for whom aMCI represents the prodromal stages of dementia.

Pages 467-478
Donald R. Royall, Raymond F. Palmer, Eric D. Vidoni, Robyn A. Honea, Jeffrey M. Burns
The Default Mode Network and Related Right Hemisphere Structures may be the Key Substrates of Dementia
Abstract: We have employed structural equation models to explicitly distinguish dementia-relevant variance in cognitive task performance (i.e., d) from the variance that is unrelated to a dementing process (i.e., g’). Together g’ and d comprise Spearman’s “g”. Although d represents only a minor fraction of the total variance in cognitive task performance, it is more strongly associated with dementia severity than is g’. In this analysis, we replicate d in a new dataspace, the University of Kansas Brain Aging Project, and associate it specifically with regional grey matter atrophy by voxel-based morphometry of magnetic resonance imaging data. The latent variable d localizes to elements of the default mode network and related structures in the R hemisphere.

Pages 479-493
Mithu Raychaudhuri, Kasturi Roy, Samir Das, Debashis Mukhopadhyay
The N-Terminal SH3 Domain of Grb2 is Required for Endosomal Localization of AβPP
Abstract: Based on the observations that Grb2 overexpression altered the trafficking route of amyloid-β protein precursor (AβPP) by inhibiting its release via exosomal vesicles, and subsequently increased its endogenous level, in the present study we aimed to elucidate the mechanism of traffic impairment and the role of different Grb2 domains in this process. We found that the N-SH3 domain of Grb2 was involved in the protein vesicular localization. The C-SH3 domain could also form very small puncta, but were not characteristic Grb2 containing vesicles. Vesicles containing the N-SH3-SH2 domain had a mixed population of early and late endosomes but C-SH3-SH2 domain containing vesicles were of early endosomal type. The N-SH3 domain therefore seems to be involved in the maturation of early endosomes to late endosomes. Almost all the features shown by overexpression of full-length type Grb2, for example, entrapment of endogenous AβPP in vesicles, affecting the turnover of AβPP in terms of decrease in exosomal release and increase in endogenous concentration of the protein, could be reproduced by the N-SH3-SH2 domain and, to a very limited extent, by the C-SH3-SH2 domain. The middle SH2 domain alone did not show any involvement in AβPP trafficking. By mutational analysis of both N and C terminal SH3 domains, attempts were made to elucidate the molecular basis of this functional anomaly.

Supplementary Data for Raychaudhuri et al. article (PDF)

Pages 495-511
Eduardo Luiz Gasnhar Moreira, Jade de Oliveira, Jean Costa Nunes, Danúbia Bonfanti Santos, Fernanda Costa Nunes, Daniella Serafim Couto Vieira, Rosa Maria Ribeiro-do-Valle, Fabrício Alano Pamplona, Andreza Fabro de Bem, Marcelo Farina, Roger Walz, Rui Daniel Prediger
Age-Related Cognitive Decline in Hypercholesterolemic LDL Receptor Knockout Mice (LDLr-/-): Evidence of Antioxidant Imbalance and Increased Acetylcholinesterase Activity in the Prefrontal Cortex
Abstract: There is increasing evidence that hypercholesterolemia during midlife may represent a predictor of subsequent mild cognitive impairments and dementia decades later. However, the exact mechanism underlying this phenomenon remains unknown since plasmatic cholesterol is not able to cross the blood-brain barrier. In the present study, we evaluated the hypothesis that cognitive impairments triggered by hypercholesterolemia during aging may be related to brain oxidative stress and altered brain acetylcholinesterase (AChE) activity. We also performed a neuropathological investigation in order to analyze whether the cognitive impairments may be associated with stroke-related features. To address these questions we used three- and fourteen-month-old low-density lipoprotein receptor-deficient mice (LDLr-/-). The current findings provide new evidence that aged LDLr-/- mice, exposed to over three-fold cholesterol levels from early life, show working, spatial reference, and procedural memory impairments, without alterations in motor function. Antioxidant imbalance and oxidative damage were evidenced by a marked increase in lipid peroxidation (thiobarbituric acid reactive substances levels) and glutathione metabolism (increase in glutathione levels, glutathione reductase, and glutathione peroxidase activities) together with a significant increase in the AChE activity in the prefrontal cortex of aged hypercholesterolemic LDLr-/- mice. Notably, hypercholesterolemia was not related to brain infarcts and neurodegeneration in mice, independent of their age. These observations provide new evidence that hypercholesterolemia during aging triggers cognitive impairments on different types of learning and memory, accompanied by antioxidant imbalance, oxidative damage, and alterations of cholinergic signaling in brain areas associated with learning and memory processes, particularly in the prefrontal cortex.

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