Volume 27, Number 4, December 2011

Pages 679-689
Hypothesis
Ming Chen, Huey T. Nguyen, Darrell R. Sawmiller
What to Look for Beyond “Pathogenic” Factors in Senile Dementia? A Functional Deficiency of Ca2+ Signaling
Abstract: We have contended that senile conditions—illnesses after age 60 and fully age-penetrating, such as tooth, hearing or memory loss—are not distinct “diseases” in medical nature, because they are caused by aging. Since the pace of aging varies among individuals and is much influenced by risk factors, senile conditions will only affect some but not all elderly. However, perhaps due to its unusually heavy burdens and tremendous social pressures, senile dementia (SD) has been singled out from other senile conditions and redefined as a curable “disease” (Alzheimer’s). This highly popular definition has thus opened a Pandora’s box that has been confusing us up until now, and warrants further scrutiny. In this article we discuss: a) what should we logically look for in SD beyond “pathogenic” factors?; b) why Ca2+, a central regulator in neurotransmission, is the converging point of the actions of many other factors in SD; c) why the functionality of Ca2+ signaling, or its vibrant wave frequency and amplitude, must undergo down-regulation during aging, but this is intriguingly accompanied by an increase of Ca2+ “levels”; d) why intervention for SD should target Ca2+ function by promoting energy metabolisms and by Ca2+ agonists such as caffeine and nicotine, but not by “antagonists” as widely believed; and e) why our study should focus on aging, not “cell death”, a seemingly attractive paradigm but perhaps too late for intervention. We also seek answers for why unproven hypotheses can become dogmas and inhibit self-correcting mechanisms of science.

Pages 691-699
Hypothesis
Ian A. Clark, Craig S. Atwood
Is TNF a Link between Aging-Related Reproductive Endocrine Dyscrasia and Alzheimer’s Disease?
Abstract: This commentary addresses a novel mechanism by which aging-related changes in reproductive hormones could mediate their action in the brain. It presents the evidence that dyotic endocrine signals modulate the expression of tumor necrosis factor (TNF) and related cytokines, and that these cytokines are a functionally important downstream link mediating neurodegeneration and dysfunction. This convergence of dyotic signaling on TNF-mediated degeneration and dysfunction has important implications for understanding the pathophysiology of AD, stroke, and traumatic brain disease, and also for the treatment of these diseases.

Pages 701-709
Ana LLoret, Mari-Carmen Badia, Esther Giraldo, Gennady Ermak, Maria-Dolores Alonso, Federico V. Pallardó, Kelvin J.A. Davies, Jose Viña
Amyloid-β Toxicity and Tau Hyperphosphorylation are Linked Via RCAN1 in Alzheimer’s Disease
Abstract: Amyloid-β peptide (Aβ) toxicity and tau hyperphosphorylation are hallmarks of Alzheimer’s disease (AD). How their molecular relationships may affect the etiology, progression, and severity of the disease, however, has not been elucidated.  We now report that incubation of fetal rat cortical neurons with Aβ upregulates expression of the Regulator of Calcineurin gene RCAN1, and this is mediated by Aβ-induced oxidative stress.  Calcineurin (PPP3CA) is a serine-threonine phosphatase that dephosphorylates tau. RCAN1 proteins inhibit this phosphatase activity of calcineurin.  Increased expression of RCAN1 also causes upregulation of glycogen synthase kinase-3β (GSK3β), a tau kinase.  Thus, increased RCAN1 expression might be expected to decrease phospho-tau dephosphorylation (via calcineurin inhibition) and increase tau phosphorylation (via increased GSK3β activity). Indeed, we find that incubation of primary cortical neurons with Aβ results in increased phosphorylation of tau, unless RCAN1 gene expression is silenced, or antioxidants are added.  Thus we propose a mechanism to link Aβ toxicity and tau hyperphosphorylation in AD: In our hypothesis, Aβ causes mitochondrial oxidative stress and increases production of reactive oxygen species, which result in an upregulation of RCAN1 gene expression.  RCAN1 proteins then both inhibit calcineurin and induce expression of GSK3β. Both mechanisms shift tau to a hyperphosphorylated state.  We also find that lymphocytes from persons whose ApoE genotype is ε4/ε4 (with high risk of developing AD) show higher levels of RCAN1 and phospho-tau than those carrying the ApoE ε3/ε3 or ε3/ε4 genotypes. Thus upregulation of RCAN1 may be a valuable biomarker for AD risk.

Pages 711-722
Jing Yang, Lisa K. Lunde, Paworn Nuntagij, Tomohiro Oguchi, Laura M.A. Camassa, Lars N.G. Nilsson, Lars Lannfelt, Yuming Xu, Mahmood Amiry-Moghaddam, Ole Petter Ottersen, Reidun Torp
Loss of Astrocyte Polarization in the Tg-ArcSwe Mouse Model of Alzheimer’s Disease
Abstract: Aquaporin-4 (AQP4) is the predominant water channel in brain and is selectively expressed in astrocytes. Astrocytic endfoot membranes exhibit tenfold higher densities of AQP4 than non-endfoot membranes, making AQP4 an excellent marker of astrocyte polarization. Loss of astrocyte polarization is known to compromise astrocytic function and to be associated with impaired water and K+ homeostasis. Here we investigate by a combination of light and electron microscopic immunocytochemistry whether amyloid deposition is associated with a loss of astrocyte polarization, using AQP4 as a marker. We used the tg-ArcSwe mouse model of Alzheimer’s disease, as this model displays perivascular plaques as well as plaques confined to the neuropil. 3D reconstructions were done to establish the spatial relation between plaques and astrocytic endfeet, the latter known to contain the perivascular pool of AQP4. Changes in AQP4 expression emerge just after the appearance of the first plaques. Typically, there is a loss of AQP4 from endfoot membranes at sites of perivascular amyloid deposits, combined with an upregulation of AQP4 in the neuropil surrounding plaques. By electron microscopy it could be verified that the upregulation reflects an increased concentration of AQP4 in those delicate astrocytic processes that abound in synaptic regions. Thus, astrocytes exhibit a redistribution of AQP4 from endfoot membranes to non-endfoot membrane domains. The present data suggest that the development of amyloid deposits is associated with a loss of astrocyte polarization. The possible perturbation of water and K+ homeostasis could contribute to cognitive decline and seizure propensity in patients with Alzheimer’s disease.

Pages 723-736
Jens Peter Reese, Philipp Heßmann, Greta Seeberg, Dajana Henkel, Pamela Hirzmann, Jürgen Rieke, Erika Baum, Frank Dannhoff, Matthias J. Müller, Frank Jessen, Monika-Balzer Geldsetzer, Richard Dodel
Cost and Care of Patients with Alzheimer’s Disease: Clinical Predictors in German Health Care Settings
Abstract: The study aims to report service use and costs for patients with Alzheimer’s disease (AD) and to explore the incremental influence of sociodemographic and illness-related determinants in ambulatory and inpatient settings within the German health care system. 395 patients with dementia were recruited at the following sites: 1) a University hospital, 2) general practitioners’ offices, 3) office-based neurologists, 4) a regional psychiatric hospital, and 5) nursing homes. Socio­demo­gra­phic, economic, and clinical parameters were assessed using a standardized questionnaire. Disease severity was measured using the Mini-Mental Status Examination and the Alzheimer's Disease Assessment Scale. Neuropsychiatric status was assessed using the Geriatric Depression Scale, the Neuropsychiatric Inventory, and the Alzheimer's Disease Cooperative-Study-Activities of Daily Living. Annual total costs were estimated to be €22,848 per patient. The most important cost component was (long-term) care, constituting about 65% of total costs. Indirect costs comprised about 12% of total costs and were mainly due to reductions in working time of caregivers. Poorer functional status was associated with higher total and caregiving costs. In multivariate analyses, we identified younger age, female gender, and impaired activities of daily living as independent predictors of higher costs. Given that care for patients with AD is complex and expensive, our models were only able to explain about 12-31% of the variability in total costs. This suggests that further social and individual factors considerably influence the costs associated with AD. Direct medical care costs and long-term care costs related differently to the patient’s clinical characteristics. Longitudinal and population-based studies are necessary for thoroughly evaluating the burden of disease.

Pages 737-742
Agnese Picco, Silvana Archetti, Michela Ferrara, Dario Arnaldi, Alessandra Piccini, Carlo Serrati, Diego di Lorenzo, Silvia Morbelli, Flavio Nobili (Handling Associate Editor: Patrizia Mecocci)
Seizures Can Precede Cognitive Symptoms in Late-Onset Alzheimer's Disease
Abstract: This study describes late-onset Alzheimer’s disease (LOAD) in the mild cognitive impairment (MCI) stage, debuting with seizures in a 72 year-old woman. Prodromal AD was consistently diagnosed with four among amyloidosis and neurodegeneration biomarkers about 1 year after onset of seizures. Genetic assessment demonstrated apolipoprotein E ε2/ε3 genotype and three intronic single nucleotide substitutions, two in presenilin 1 and one in amyloid-β protein precursor genes. This case of seizures at onset of LOAD with severe signs of brain amyloidosis and neurodegeneration but with just MCI leads to a re-appraisal of the intriguing relationship between AD pathology and neuron excitability in humans.

Pages 743-752
Edward Rockenstein, Kiren Ubhi, Edith Doppler, Philipp Novak, Herbert Moessler, Bin Li, Julie Blanchard, Inge Grundke-Iqbal, Khalid Iqbal, Michael Mante, Anthony Adame, Leslie Crews, Eliezer Masliah
Regional Comparison of the Neurogenic Effects of CNTF-Derived Peptides and Cerebrolysin in AβPP Transgenic Mice
Abstract: Adult neurogenesis, the production of new neurons in certain brain regions, is known to decrease with age and the loss of neurogenic potential has been implicated in Alzheimer’s disease (AD), a leading cause of dementia in the elderly. Cerebrolysin (CBL) has been shown to increase neurogenesis in models of stroke and AD. CBL is composed of small peptides with activity similar to neurotrophic factors including ciliary neurotrophic factor (CNTF), which may mediate its neurogenic effects. This study compares the effects of CBL and two peptides with corresponding to an active region of CNTF (Peptide 6 and 6A) across neurogenic brain regions in amyloid-β protein precursor (AβPP) transgenic (tg) mice. Both CBL and Peptides 6 and 6A were able to increase the numbers of neuroblasts (DCX+ cells) and BrdU+ cells in a regionally specific manner across the subventricular zone, olfactory bulb, and hippocampus. The increased generation of new cells and cell survival in animals treated with Peptides 6 and 6A was accompanied by an increase in PCNA+ cells. In contrast, AβPP tg mice treated with CBL displayed reduced levels of TUNEL staining, while levels of PCNA were unaltered. Collectively these results demonstrate that while CBL and Peptides 6 and 6A all potentiate neurogenesis in the AβPP tg mice, their relative modes of action may differ with CBL associated with reduced apoptosis and Peptides 6 and 6A working by augmenting cell proliferation. These results are consistent with a potential therapeutic relevance for Peptides 6 and 6A in AD and other disorders characterized by neurogenic deficits.

Pages 753-765
Maitrayee Sinha, Prajna Behera, Pritha Bhowmick, Kalpita Banerjee, Sumitran Basu, Sasanka Chakrabarti (Handling Associate Editor: Debomoy Lahiri)
Aging Promotes Amyloid-β Peptide Induced Mitochondrial Dysfunctions in Rat Brain: A Molecular Link Between Aging and Alzheimer’s Disease
Abstract: The entangled relationship of brain aging, mitochondrial dysfunction, and amyloid-β peptide (Aβ42) toxicity occupies the center stage in the pathogenesis of Alzheimer’s disease (AD). The present study examines some of the toxic effects of Aβ42 on brain mitochondria and provides evidence that aged brain mitochondria are significantly more vulnerable to Aβ42 toxicity. In particular, the study has shown that the aggregated, but not the monomeric, form of Aβ42 in varying concentrations (10–40 μM) during in vitro incubation causes a loss of mitochondrial membrane potential, a decrease in phosphorylation capacity and ATP synthesis, and the release of cytochrome c from the mitochondria but without any noticeable change in the activities of respiratory chain complexes. Such effects of Aβ42 are strikingly more conspicuous on aged rat (22–24 months) brain mitochondria compared to that on brain mitochondria of young rats (4-6 months). More interestingly is the observation that in contrast to young rat brain mitochondria, a significantly higher level of Aβ42 remains associated with aged brain mitochondria under basal incubation condition as well as after exposure to exogenously added peptide. Extrapolated to an in vivo scenario, the results have clear implications in AD pathogenesis and also partly explain why brain aging is a dominant risk factor for this disease condition.

Pages 767-779
Alison J. Gauci, Mario Caruana, Armin Giese, Charles Scerri, Neville Vassallo (Handling Associate Editor: Othman Ghribi)
Identification of Polyphenolic Compounds and Black Tea Extract as Potent Inhibitors of Lipid Membrane Destabilization by Aβ42 Aggregates
Abstract: Amyloid-β (Aβ) aggregation is a recognized key process in the pathogenesis of Alzheimer’s disease (AD). Misfolded Aβ peptides self-assemble into higher-order oligomers that compromise membrane integrity, leading to synaptic degeneration and neuronal cell death. The main aim of this study was to explore whether small-molecule compounds and black tea extract can protect phospholipid membranes from disruption by Aβ aggregates. We first established a robust protocol for aggregating Aβ42 peptides into a range of oligomers that efficiently permeabilized small unilamellar liposomes. Next, 15 natural plant polyphenolic compounds, 8 N′-benzylidene-benzohydrazide (NBB) compounds and black tea extract were assessed for their ability to antagonize liposome permeabilization by the Aβ42 oligomers.  Our data indicates that black tea extract, the flavones apigenin and baicalein, and the stilbene nordihydroguaiaretic acid (NDGA) are indeed potent inhibitors. Taking into consideration the results of all the small-molecule polyphenols and NBB compounds, it can be proposed that a dihydroxyphenyl ring structure, alone or as part of a flavone scaffold, is particularly effective for protection against membrane damage by the Aβ42 oligomers. Given the critical role of membrane perforation in the neurodegenerative cascade, these conclusions may guide the design and development of novel therapeutic drugs in AD.

Pages 781-790
Miryam Carecchio, Chiara Fenoglio, Francesca Cortini, Cristoforo Comi, Luisa Benussi, Roberta Ghidoni,  Barbara Borroni, Milena De Riz, Maria Serpente, Claudia Cantoni, Massimo Franceschi, Valentina Albertini, Francesco Monaco, Innocenzo Rainero, Giuliano Binetti, Alessandro Padovani, Nereo Bresolin, Elio Scarpini, Daniela Galimberti (Handling Associate Editor: Benedetta Nacmias)
Cerebrospinal Fluid Biomarkers in ProgranulinMutations Carriers
Abstract: Cerebrospinal fluid (CSF) biomarkers (Aβ1-42, total tau, P-181 tau) are currently used to support a clinical diagnosis of Alzheimer’s disease (AD). The CSF profile in frontotemporal lobar degeneration (FTLD) caused by Progranulin (GRN)mutation is unknown. We assessed CSF biomarkers in 145 AD, 140 FTLD (20 GRN positive, 120 GRN negative) patients, and 38 controls. Taking into account the reference values used in clinical practice, GRN mutation carriers and controls did not differ significantly for any biomarker, whereas GRN negative FTLD patients had higher tau levels than controls (p<0.001) and patients carrying GRN Thr272fs mutation (p=0.033, Chi-Square test). Comparing CSF biomarkers mean values among groups, total tau was significantly increased in GRN negative FTLD and in mutation carriers compared with controls (p<0.001). P-181 tau CSF was increased in AD patients and in GRN negative FTLD compared with controls (p<0.001), but not in 17 patients carrying the Thr272fs mutation. 88.2% of mutation carriers had normal CSF tau, despite the neurodegenerative nature of FTLD. Our results suggest that GRN mutation carriers have normal or borderline CSF biomarkers. In patients with an AD-like phenotype but normal or borderline CSF biomarkers, a diagnosis of FTLD-U caused by GRN mutations should be considered.

Pages 791-797
Chiara Cerami, Alessandra Marcone, Daniela Galimberti, Chiara Villa, Elio Scarpini, Stefano F. Cappa (Handling Associate Editor: Benedetta Nacmias)
From Genotype to Phenotype: Two Cases of Genetic Frontotemporal Lobar Degeneration with Premorbid Bipolar Disorder
Abstract: Frontotemporal lobar degeneration (FTLD) is a common early-onset dementia, which shows highly heterogeneous phenotypic presentations. Although an autosomal dominant transmission can be found only in about 10% cases, familial aggregation is frequently observed in FTLD. Recently, the progranulin gene (GRN) was reported to be involved in the disease pathogenesis. We describe two clinically different, apparently sporadic FTLD cases, sharing the previously described GRN mutation g.11019_11022delCACT (relative to nt1, NCBI NG_007886.1), alias Thr272fs, with a premorbid psychiatric history. Both patients are males and were in their sixties when diagnosed clinically with, respectively, the behavioral variant of frontotemporal dementia (bvFTD) and progressive nonfluent aphasia (PNFA). In both cases, the medical history revealed the presence of bipolar spectrum disorders. Mutations in GRN are considered to be a major cause of FTLD. However, the phenotypes associated with these mutations are highly variable. Our description of two novel FTLD genetic cases confirms the high frequency of the g.11019_11022delCACT mutation in Northern Italy. On this basis, we recommend to consider the presence of this mutation as a possible cause of the disease, particularly in patients with premorbid psychiatric symptoms.

Pages 799-807
Jun-Wen Guan, Chang-Quan Huang, Yong-Hong Li, Chao-Min Wan, Chao You, Zheng-Rong Wang, Yan-You Liu, Qing-Xiu Liu
No Association Between Hypertension and Risk for Alzheimer’s Disease: A Meta-Analysis of Longitudinal Studies
Abstract: This study examined the association between hypertension and AD by using a quantitative meta-analysis of longitudinal studies. EMBASE and MEDLINE were searched for articles published up to February 2011. All studies that examined the association of hypertension or antihypertensive medication use with the onset of AD were included. Pooled relative risks (RR) were calculated using fixed and random effects models. 12 studies met our inclusion criteria for this meta-analysis. All subjects were without dementia at baseline. Among them, 9 studies compared the incidence of AD between subjects with (7,270) and without (8,022) hypertension. The quantitative meta-analysis showed that there was no significant difference in incidence of AD (RR:1.02, 95% confidence interval (CI): 0.91-1.14) between subjects with and without hypertension. 7 studies compared the incidence of AD between subjects with (8,703) and without (13,041) antihypertensive medication use. The quantitative meta-analysis showed that there was no significant difference in incidence of AD (RR:0.90, 95% CI: 0.79-1.03) between subjects with and without antihypertensive medication use. The quantitative meta-analysis showed that neither hypertension nor antihypertensive medication use was associated with risk for incident AD.

Pages 809-817
Federico Licastro, Ilaria Carbone, Manuela Ianni, Elisa Porcellini (Handling Associate Editor: Calogero Caruso)
Gene Signature in Alzheimer’s Disease and Environmental Factors: The Virus Chronicle
Abstract: Genome wide association investigations from large cohorts of patients with Alzheimer’s disease (AD) and non demented controls (CTR) showed that a limited set of genes were associated (p > l0-5) with the disease. A very recent study from our group showed that an additional limited group of SNP in selected genes were associated with AD. In this report we argue that the association of these genes with AD is suggestive of a pivotal role of environmental factors in the pathogenesis of the disease and one of these factors is virus infection. In other words, the genetic signature revealed by genome wide association (GWA) studies discloses a network of genes that might influence the ability of the central nervous system to cope with and fight against the invasion by virus of the herpes family. In fact, Nectin-2 (NC-2); apolipoprotein E (APOE); glycoprotein carcinoembryonic antigen related cell adhesion molecule-16 (CEACAM-16); B-cell lymphoma-3 (Bcl-3); translocase of outer mitochondrial membrane 40 homolog (T0MM-40); complement receptor-1 (CR-l); APOJ or clusterin and C-type lectin domain A family-16 member (CLEC-16A); Phosphatidyl inositol- binding clathrin assembly protein gene (PICALM); ATP-bonding cassette, sub family A, member 7 (ABCA7); membrane spanning A4 (MSA4); CD2 associated protein (CD2AP); cluster of differentiation 33 (CD33); and ephrin receptor A1 (EPHA1) result in a genetic signature that might affect individual brain susceptibility to infection by the herpes virus family during aging, leading to neuronal loss, inflammation, and amyloid deposition.

Pages 819-833
Syed Waseem Bihaqi, Hui Huang, Jinfang Wu, Nasser H. Zawia
Infant Exposure to Lead (Pb) and Epigenetic Modifications in the Aging Primate Brain: Implications for Alzheimer’s Disease
Abstract: The beginnings of late onset Alzheimer's disease (LOAD) are still unknown; however, the progressive and latent nature of neurodegeneration suggests that the triggering event occurs earlier in life. Aging primates exposed to lead (Pb) as infants exhibited an overexpression of the amyloid-β protein precursor (AβPP), amyloid-β (Aβ) and enhanced pathologic neurodegeneration. In this study, we measured the latent expression of a wide array of brain-specific genes and explored whether epigenetic pathways mediated such latent molecular and pathological changes. We analyzed the levels of proteins associated with DNA methylation, i.e., DNA methyltransferase 1 (Dnmt1), DNA methyltransferase3a (Dnmt3a), methyl-CpG binding protein-2 (MeCP2) and those involved in histone modifications (acetylated and methylated histones). We monitored the expression profiles of these intermediates across the lifespan and analyzed their levels in 23-year-old primate brains exposed to Pb as infants. Developmental Pb exposure altered the gene expression of the arrayed genes, which were predominately repressed, with fewer upregulated genes. The latent induction and repression of genes was accompanied by a significant decrease in the protein levels of Dnmts, MeCP2, and proteins involved in histone modifications. The attenuation of DNA methylation enzymes is consistent with hypomethylating effects, which promote upregulation of the genes, while the alterations in the histone modifiers are associated with the repression of genes. Hence, we deduce that early life exposure to Pb can reprogram gene expression resulting in both upregulation and down-regulation of genes through alternate epigenetic pathways contributing to an enhancement in neurodegeneration in old age.

Pages 835-843
Ali Taghavi, Samir Nasir, Marcus Pickhardt, Roland Heyny-von Hauβen, Sabine Krause, Gerhard Mall, Eckhard Mandelkow, Eva-Maria Mandelkow, Boris Schmidt
N’-Benzylidene-Benzohydrazides as Novel and Selective Tau-PHF Ligands
Abstract: The structure activity relationship of N´-benzylidene-benzohydrazide (NBB) binding to tau and paired helical filament (PHF) proteins as well as amyloid-β1-42 fibrils indicate differential selectivity for these protein aggregates. The ability of the compounds to stain neurofibrillary tangles and senile plaques isolated from human AD brain was investigated histochemically. These studies resulted in several tau-PHF and amyloid-β1-42 fibril selective ligands respectively. Supported by these results, we rationalized a model for the design of selective ligands for tau, PHF, and amyloid-β1-42 fibrils.

Pages 845-851
Julien Dumurgier, Claire Paquet, Katell Peoc’h, Pauline Lapalus,  François Mouton-Liger, Sarah Benisty, Stéphanie Chasseigneaux, Hughes Chabriat, Jacques Hugon
CSF Aβ1-42 Levels and Glucose Metabolism in Alzheimer’s Disease
Abstract: Glucose dysmetabolism has been consistently associated with an increased risk of cognitive disorders, and brain insulin resistance could play a role in Alzheimer’s disease (AD) pathogenesis. Recent evidence suggests that cerebrospinal fluid (CSF) biomarkers may reflect the brain pathology in AD. We have investigated the relationship between CSF concentrations of amyloid-β peptide 1-42 (Aβ1-42), total tau, and phosphorylated tau (ptau-181) and plasma and CSF glucose levels in a cohort of 94 newly diagnosed non-diabetics AD patients. We report that CSF Aβ1-42 level was inversely associated with CSF to plasma glucose ratio (Spearman’s coefficient = -0.27, p=0.008). This relationship remained after adjustment for age, gender, body mass index, hypertension, and MMSE score (β [SE] of linear regression = -0.93 [0.37], p=0.01). In stratified analysis, this relationship was observed only in patients who did not carry the apolipoprotein E4 allele. No significant relationship was found between glucose levels and total tau or phosphorylated tau 181. These results support the idea that a link between glucose dysmetabolism and the amyloid pathway may exist in the pathogenesis of AD.

Pages 853-869
Meryem Lebbadi, Carl Julien, Alix Phivilay, Cyntia Tremblay, Vincent Emond, Jing X Kang, Frédéric Calon (Handling Associate Editor: Othman Ghribi)
Endogenous Conversion of Omega-6 into Omega-3 Fatty Acids Improves Neuropathology in an Animal Model of Alzheimer’s Disease
Abstract: Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) reduces amyloid-β (Aβ) and tau pathology and improves cognitive performance in animal models of Alzheimer’s disease (AD). To exclude confounding variables associated with the diet, we crossed 3xTg-AD mice (modeling AD neuropathology) with transgenic Fat-1 mice that express the fat-1 gene encoding a PUFA desaturase, which endogenously produces n-3 PUFA from n-6 PUFA. The expression of fat-1 shifted the n-3:n-6 PUFA ratio upward in the brain (+11%, p < 0.001), including docosahexaenoic acid (DHA; +5%, p< 0.001) in 20 month-old mice. The expression of fat-1 decreased the levels of soluble Aβ42 (-41%, p < 0.01) at 20 months without reducing the level of insoluble forms of Aβ40 and Aβ42 in the brain of 3xTg-AD mice. The 3xTg-AD/Fat-1 mice exhibited lower cortical levels of both soluble (-25%, p < 0.05) and insoluble phosphorylated tau (-55%, p< 0.05) compared to 3xTg-AD mice, but only in 20 month-old animals. Whereas a decrease of calcium/calmodulin-dependent protein kinase II was observed in 3xTg-AD/Fat-1 mice (-39%, p< 0.05), altered tau phosphorylation could not be related to changes in glycogen synthase kinase 3β, cyclin-dependent kinase 5, or protein phosphatase type-2A enzymatic activity. In addition, the expression of the fat-1 transgene prevented the increase of glial fibrillary acidic protein (-37%, p< 0.01) observed in 20 month-old 3xTg-AD mice. In conclusion, the expression of fat-1 in 3xTg-AD mice increases brain DHA and induces biomarker changes that are consistent with a beneficial effect against an AD-like neuropathology.

Supplementary Data for Lebbadi et al. article (PDF)

Pages 871-883
Michela Guglielmotto, Debora Monteleone, Luca Giliberto, Michele Fornaro , Roberta Borghi, Elena Tamagno, Massimo Tabaton
Amyloid-β42 Activates the Expression of BACE1 Through the JNK Pathway
Abstract: The sequential endoproteolytic cleavages operated by the gamma-secretase and the β-secretase (BACE1) on the amyloid-β protein precursor (AβPP) result in the production of the amyloid-β (Aβ) species, with two C-terminal variants, at residue 40 or at residue 42. Accumulation in brain tissue of small, soluble aggregates of Aβ42 is the major pathogenic event of Alzheimer’s disease (AD). However, the physiologic activity of Aβ peptides is still elusive. Here, we show that expression of BACE1 is regulated by Aβ42, which augments BACE1 gene transcription through the JNK/c-jun signaling pathway. Of note, Aβ40 has much less effect on BACE1 expression. These findings unveil a positive feedback loop in which gamma-secretase cleavage of AβPP releases a functionally-active peptide, Aβ42, that promotes BACE1 transcription. Thus, gene expression induced by Aβ42 may have implications in the neuronal dysfunction and degeneration that occurs in AD.

Pages 885-895
J. Wesson Ashford, Emily Gere, Peter J. Bayley
Measuring Memory in Large Group Settings Using a Continuous Recognition Test
Abstract: Memory function generally deteriorates with age, and memory impairments are a common symptom of serious illness such as dementia. Although screening tests are widely used throughout Medicine, they are not yet commonly used to detect memory impairments. The objective of this study was to characterize an audience-based memory test suitable for administration to a large number of individuals simultaneously. A continuous recognition test was developed to assess memory function in audiences using a slide-show in which 50 images were presented, of which 25 were repeated. Audience members responded by recording if an image was a repetition. The test was administered to a total of 1018 participants at 25 sites with an average audience size of 41 individuals (range = 9–142). A total of 868 individuals aged 40–97 y completed the test appropriately and provided their age, education level, and gender. Recognition memory as measured by discriminability (d’) showed a significant decline with age (40-49 y old, d’ = 3.51; 90-99 y old, d’ = 1.95, p < 0.001) together with a greater than three-fold increase in variability. Individuals with less than 12 y of education had lower scores than those with more education (d’ = 2.13 vs. 2.88, respectively, p < 0.001). These results are consistent with the known effects of age and education on memory. There were no significant effects of gender on test performance. Such memory tests represent a practical and novel approach to screen for the signs of early dementia.

Supplementary Data for Ashford et al. article (PDF)

Pages 897-907
Tiffany A. Greenwood, Michal S. Beeri, James Schmeidler, Daniel Valerio, Henriette Raventós, Lara Mora-Villalobos, Karla Camacho, José R. Carrión-Baralt, Gary Angelo, Laura Almasy, Mary Sano, Jeremy M. Silverman (Handling Associate Editor: Benedetta Nacmias)
Heritability of Cognitive Functions in Families of Successful Cognitive Aging Probands from the Central Valley of Costa Rica
Abstract: We sought to identify cognitive phenotypes for family/genetic studies of successful cognitive aging (SCA; maintaining intact cognitive functioning while living to late old age). We administered a battery of neuropsychological tests to nondemented nonagenarians (n=65; mean age= 93.4±3.0) and their offspring (n=188; mean age=66.4±5.0) from the Central Valley of Costa Rica. After covarying for age, gender, and years of education, as necessary, heritability was calculated for cognitive functions at three pre-defined levels of complexity: specific neuropsychological functions (e.g., delayed recall, sequencing), three higher level cognitive domains (memory, executive functions, attention), and an overall neuropsychological summary. The highest heritability was for delayed recall (h2=0.74, se=0.14, p < 0.0001) but significant heritabilities involving memory were also observed for immediate recall (h2=0.50), memory as a cognitive domain (h2=0.53), and the overall neuropsychological summary (h2=0.42).  Heritabilities for sequencing (h2=0.42), fluency (h2=0.39), abstraction (h2=0.36), and the executive functions cognitive domain (h2=0.35) were also significant. In contrast, the attention domain and memory recognition were not significantly heritable in these families. Among the heritable specific cognitive functions, a strong pleiotropic effect (i.e., evidence that these may be influenced by the same gene or set of genes) for delayed and immediate recall was identified (bivariate statistic = 0.934, p< 0.0001) and more modest but significant effects were found for four additional bivariate relationships. The results support the heritability of good cognitive function in old age and the utilization of several levels of phenotypes, and they suggest that several measures involving memory may be especially useful for family/genetic studies of SCA.

Pages 909-922
Noel G Faux, Kathryn A Ellis, Lorine Porter, Chris J Fowler, Simon M Laws, Ralph N Martins, Kelly K Pertile, Alan Rembach, Chris C Rowe , Rebecca L Rumble, Cassandra Szoeke, Kevin Taddei, Tania Taddei, Brett O Trounson, Victor L Villemagne, Vanessa Ward, David Ames, Colin L Masters, the AIBL research group, Ashley I Bush
Homocysteine, Vitamin B12, and Folic Acid Levels in Alzheimer’s Disease, Mild Cognitive Impairment, and Healthy Elderly: Baseline Characteristics in Subjects of the Australian Imaging Biomarker Lifestyle Study
Abstract: There is some debate regarding the differing levels of plasma homocysteine, vitamin B12 and serum folate between healthy controls (HC), mild cognitive impairment (MCI), and Alzheimer's disease (AD). As part of the Australian Imaging Biomarker Lifestyle (AIBL) study of aging cohort, consisting of 1,112 participants (768 HC, 133 MCI patients, and 211 AD patients), plasma homocysteine, vitamin B12, and serum and red cell folate were measured at baseline to investigate their levels, their inter-associations, and their relationships with cognition. The results of this cross-sectional study showed that homocysteine levels were increased in female AD patients compared to female HC subjects (+16%, p-value < 0.001), but not in males. Red cell folate, but not serum folate, was decreased in AD patients compared to HC (-10%, p-value = 0.004). Composite z-scores of short- and long-term episodic memory, total episodic memory, and global cognition all showed significant negative correlations with homocysteine, in all clinical categories. Increasing red cell folate had a U-shaped association with homocysteine, so that high red cell folate levels were associated with worse long-term episodic memory, total episodic memory, and global cognition. These findings underscore the association of plasma homocysteine with cognitive deterioration, although not unique to AD, and identified an unexpected abnormality of red cell folate.

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