18, Number 4, December 2009
Melita Salkovic-Petrisic, Jelena Osmanovic, Edna Grünblatt, Peter Riederer, Siegfried Hoyer
Modeling Sporadic Alzheimer’s Disease: The Insulin Resistant Brain State Generates Multiple Long-Term Morphobiological Abnormalities Inclusive Hyperphosphorylated Tau Protein and Amyloid-β. A Synthesis.
Abstract: Nosologically, Alzheimer’s disease (AD) is not a single disorder. Missense gene mutations involved in increased formation of the amyloid-β protein precursor derivatives amyloid-β (Aβ)1-40 and Aβ1-42/43 lead to autosomal dominant familial AD, found in the minority of AD cases. However, millions of subjects suffer from sporadic AD (sAD) of late onset, for which no convincing evidence suggests Aβ as the primary disease-generating compound. Environmental factors operating during pregnancy and postnatally may affect susceptibility genes and stress factors (e.g., cortisol), consequently affecting brain development both structurally and functionally, causing disorders becoming manifest late in life. With aging, a desynchronization of biological systems may result, increasing further brain entropy/declining criticality. In sAD, this desynchronization may involve stress components, cortisol and noradrenaline, reactive oxygen species, and membrane damage as major candidates causing an insulin resistant brain state with decreased glucose/energy metabolism. This further leads to a derangement of ATP-dependent cellular and molecular work, of the cell function in general, as well as derangements in the endoplasmic reticulum/Golgi apparatus, axon, synapses, and membranes, in particular. A self-propagating process is thus generated, including the increased formation of hyperphosphorylated tau-protein and Aβ as abnormal terminal events in sAD rather than causing the disorder, as elaborated in the review.
Carmen Antúnez, Mercé Boada, Jesús López-Arrieta, Reposo Ramirez-Lorca, Isabel Hernández, Juan Marín, Pablo Martínez-Lage, Antonio González-Pérez, José Jorge Galan, Javier Gayán, Luis M. Real, Agustín Ruiz
GOLPH2Gene Markers are Not Associated with Alzheimer’s Disease in a Sample of the Spanish Population
Abstract: GOLPH2 gene SNP variants Rs10868366 and Rs7019412 were reported to decrease the risk of Alzheimer’s disease in a recent Whole Genome Association Study. We have investigated these genetic variants in 2470 individuals from Spain to conduct an independent replication study of the proposed SNP markers. We found no evidence of association between GOLPH2 markers and susceptibility to Alzheimer’s disease in our series. We concluded that GOLPH2 gene does not contribute to risk of disease in this study sample.
Ines Moreno-Gonzalez, David Baglietto-Vargas, Raquel Sanchez-Varo, Sebastián Jiménez, Laura Trujillo-Estrada, Elisabeth Sanchez-Mejias, Juan Carlos del Rio, Manuel Torres, Manuel Romero-Acebal, Diego Ruano, Marisa Vizuete, Javier Vitorica, Antonia Gutierrez
Extracellular Amyloid-β and Cytotoxic Glial Activation Induce Significant Entorhinal Neuron Loss in Young PS1M146L/APP751SL Mice
Abstract: Here we demonstrated that extracellular, not intracellular, amyloid-β (Aβ) and the associated cytotoxic glial neuroinflammatory response are major contributors to early neuronal loss in a PS1xAPP model. A significant loss of principal (27%) and SOM/NPY (56-46%) neurons was found in the entorhinal cortex at 6 months of age. Loss of principal cells occurred selectively in deep layers (primarily layer V) whereas SOM/NPY cell loss was evenly distributed along the cortical column. Neither layer V pyramidal neurons nor SOM/NPY interneurons displayed intracellular Aβ immunoreactivity, even after formic acid retrieval; thus, extracellular factors should be preferentially implicated in this selective neurodegeneration. Amyloid deposits were mainly concentrated in deep layers at 4-6 months, and of relevance was the existence of a potentially cytotoxic inflammatory response (TNFα, TRAIL, and iNOS mRNAs were upregulated). Moreover, non-plaque associated activated microglial cells and reactive astrocytes expressed TNFα and iNOS, respectively. At this age, in the hippocampus of some animals, extracellular Aβ induced a non-cytotoxic glial activation. The opposite glial activation, at the same chronological age, in entorhinal cortex and hippocampus strongly support different mechanisms of disease progression in these two regions highly affected by Aβ pathology.
Natalia Loskutova, Robyn A. Honea, Eric D. Vidoni, William M. Brooks, Jeffrey M. Burns
Bone Density and Brain Atrophy in Early Alzheimer’s Disease
Abstract: Studies suggest a link between bone loss and Alzheimer’s disease. To examine bone mineral density (BMD) in early Alzheimer’s disease (AD) and its relationship to brain structure and cognition, we evaluated 71 patients with early stage AD (Clinical Dementia Rating (CDR) 0.5 and 1) and 69 non-demented elderly control participants (CDR 0). Measures included whole body BMD by dual energy x-ray absorptiometry (DXA) and normalized whole brain volumes computed from structural MRI scans. Cognition was assessed with a standard neuropsychological test battery. Mean BMD was lower in the early AD group (1.11 ± 0.13) compared to the non-demented control group (1.16 ± 0.12, p=0.02), independent of age, sex, habitual physical activity, smoking, depression, estrogen replacement, and apolipoprotein E4 carrier status. In the early AD group, BMD was related to whole brain volume (b=0.18, p=0.03). BMD was also associated with cognitive performance, primarily in tests of memory (logical memory [b=0.15, p=0.04], delayed logical memory [b=0.16, p=0.02], and the selective reminding task, free recall [b=0.18, p=0.009]). BMDy is reduced in the earliest clinical stages of AD and associated with brain atrophy and memory decline, suggesting that central mechanisms may contribute to bone loss in early AD.
Flaubert Tchantchou, Pascale N. Lacor, Zhiming Cao, Lixing Lao, Yan Hou, Changhai Cui, William L. Klein, Yuan Luo (Communicated by Thomas Shea)
Stimulation of Neurogenesis and Synaptogenesis by Bilobalide and Quercetin via Common Final Pathway in Hippocampal Neurons
Abstract: Loss of synapses has been correlated with dementia in Alzheimer’s disease (AD) as an early event during the disease progression. Hence, synaptogenesis and neurogenesis in adulthood could serve as a therapeutic target for the prevention and treatment of AD. Recently, we have demonstrated enhanced hippocampal neurogenesis by oral administration of Ginkgo biloba extract (EGb 761) to a mouse model of AD. This study aims to identify the constituents that contribute to EGb 761-induced neurogenesis. Among the constituents tested, bilobalide and quercetin significantly increased cell proliferation in the hippocampal neurons in a dose-dependent manner. Bilobalide and quercetin also enhanced phosphorylation of cyclic-AMP Response Element Binding Protein (CREB) in these cells, and elevated the levels of pCREB and , brain-derived neurotrophic factor in mice brain. Immunofluorescence staining of synaptic markers shows remarkable dendritic processes in hippocampal neurons treated with either quercetin or bilobalide. Furthermore, both constituents restored amyloid-β oligomers (also known as ADDL)-induced synaptic loss and phosphorylation of CREB. The present findings suggest that enhanced neurogenesis and synaptogenesis by bilobalide and quercetin may share a common final signaling pathway mediated by phosphorylation of CREB. Despite a recent report showing that EGb 761 was insufficient in prevent dementia, its constituents still warrant future investigation.
Xiao-Hui Yang, Han-Chang Huang, Lin-Chen, Wei-Xu, Zhao-Feng Jiang (Communicated by Ralph Martins)
Coordinating to Three Histidine Residues: Cu(II) Promotes Oligomeric and Fibrillar Amyloid-β Peptide to Precipitate in a Non-β Aggregation Way
Abstract: Cu(II) has been shown in vitro to profoundly promote the aggregation of amyloid-β peptide (Aβ), a key pathological event in Alzheimer’s disease. We investigated both the effect of Cu(II) on the secondary structure transformation of Aβ and the probable residues involved in the chelation to Cu(II). The effect of Cu(II) on Aβ was analyzed by the circular dichroism spectra, Th-T fluorescence, and sedimentation assay and the results indicated that Cu(II) could disrupt the already formed β-sheet structure, convert β-sheeted aggregates into non-β-sheeted aggregates and promote oligomeric Aβ to precipitate in a non-β-sheeted aggregation way. Additionally, we confirmed that the function of Cu(II) discussed above was achieved through its interaction with His6, His13, and His14 by investigating with an Aβ mutant, 23,6,13,14Aβ1-40.
Emily House, Matthew Mold, Joanna Collingwood, Alex Baldwin, Steven Goodwin, Christopher Exley
Copper Abolishes the β-Sheet Secondary Structure of Preformed Amyloid Fibrils of Amyloid-β42
Abstract: The observation of the co-deposition of metals and amyloid-β42 (Aβ42) in brain tissue in Alzheimer’s disease prompted a myriad of investigations into the role played by metals in the precipitation of this peptide. Copper is bound by monomeric Aβ42 and upon precipitation of the copper-peptide complex thereby prevents Aβ42 from adopting a β-sheet secondary structure. Copper is also bound by β-sheet conformers of Aβ42, and herein we have investigated how this interaction affects the conformation of the precipitated peptide. Copper significantly reduced the thioflavin T fluorescence of aged, fibrillar Aβ42 with, for example, a 20-fold excess of the metal resulting in a ca 90% reduction in thioflavin T fluorescence. Transmission electron microscopy showed that copper significantly reduced the quantities of amyloid fibrils while Congo red staining and polarized light demonstrated a copper-induced abolition of apple-green birefringence. Microscopy under cross-polarized light also revealed the first observation of spherulites of Aβ42. The size and appearance of these amyloid structures were found to be very similar to spherulites identified in Alzheimer’s disease tissue. The combined results of these complementary methods strongly suggested that copper abolished the β-sheet secondary structure of pre-formed, aged amyloid fibrils of Aβ42. Copper may protect against the presence of β-sheets of Aβ42 in vivo, and its binding by fibrillar Aβ42 could have implications for Alzheimer’s disease therapy.
Julius Popp, Piotr Lewczuk, Michael Linnebank, Gabriela Cvetanovska, Yvo Smulders, Heike Kölsch, Ingo Frommann, Johannes Kornhuber, Wolfgang Maier, Frank Jessen (Communicated by Thomas Shea)
Homocysteine Metabolism and Cerebrospinal Fluid Markers for Alzheimer’s Disease
Abstract: Disturbed homocysteine metabolism is a risk factor for Alzheimer’s disease (AD) and may contribute to the disease pathophysiology by increasing both amyloid-β (Aβ) production and phosphorylated tau (P-tau) accumulation. Here, we evaluated the relationship between the cerebrospinal fluid (CSF) concentrations of homocysteine (Hcys), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and 5-methyltetrahydrofolate (5-MTHF), and the markers for AD pathology, amyloid-β (Aβ)1-42 and P-tau181, in 98 cognitively healthy subjects aged 16-81 years and 54 AD patients. In multivariate regression tests including age, gender, creatinine, and presence of the apolipoprotein E ε4 allele, P-tau181 was associated with SAH (β=0.490; p<0.001), 5-MTHF (β=-0.273; p=0.010) levels, and SAM/SAH ratio (β=-0.319; p=0.013) in controls, and with SAH (β=0.529; p=0.001) in AD patients. The levels of Aβ1-42 were not associated with the CSF concentrations of Hcys, SAM, SAH, or 5-MTHF neither in the AD nor in the control group. The results suggest that alteration of the homocysteine metabolism is related to increased accumulation of phosphorylated tau and may contribute to the neurofibrillary pathology in normal aging and in AD.
Alessandra Pani*, Sandra Dessì*, Giacomo Diaz*, Paolo La Colla, Claudia Abete, Claudia Mulas, Fabrizio Angius, Maria D. Cannas, Christina D. Orru, Pier Luigi Cocco, Antonella Mandas, Paolo Putzu, Anna Laurenzana, Cristina Cellai, Antonio Mitidieri Costanza, Antonio Bavazzano, Alessandra Mocali, Francesco Paoletti* *These authors contributed equally to this work.
Altered Cholesterol Ester Cycle in Skin Fibroblasts from Patients with Alzheimer’s Disease
Abstract: Intracellular cholesterol metabolism was reported to modulate amyloid-β (Aβ) generation in Alzheimer’s disease (AD). Results presented herein demonstrated that, like brain cells, cultured skin fibroblasts from AD patients contained more cholesterol esters than fibroblasts from healthy subjects. Particularly, Oil Red-O, Nile Red, and filipin staining highlighted higher levels of neutral lipids which responded to inhibitors of acyl-coenzyme A:cholesterol acyl-transferase (ACAT-1), associated with an increase in free cholesterol. ACAT-1 mRNA levels increased significantly in AD fibroblasts, whereas those of sterol regulatory element binding protein-2, neutral cholesterol ester hydrolase, and ATP-binding cassette transporter member 1 were markedly down-regulated. Instead, mRNA levels of low-density lipoprotein receptor, hydroxy-methyl-glutaryl-coenzyme A reductase, caveolin-1, and amyloid-β protein precursor (AβPP) were virtually unchanged. Notably, mRNA levels of both β-site AβPP-cleaving enzyme 1 (BACE1) and neprilysin were significantly down-regulated. An increase in Aβ40 and Aβ42 immunostaining and a decrease in BACE1 active form were also found in AD versus control fibroblasts. Altogether, these findings support the hypothesis that the derangement of cholesterol homeostasis is a systemic alteration involving central but also peripheral cells of AD patients, and point to cholesterol esters levels in AD fibroblasts as an additional metabolic hallmark useful in the laboratory and clinical practice.
Paloma Goñi-Oliver, Jesús Avila and Félix Hernández
Memantine Inhibits Calpain-Mediated Truncation of GSK-3 Induced by NMDA: Implications in Alzheimer’s Disease
Abstract: Deregulation of glycogen synthase kinase-3 (GSK-3) activity is believed to play a key role in the pathogenesis of Alzheimer’s disease (AD). GSK-3 activity is regulated by phosphorylation and through interaction with GSK-3-binding proteins. Previously, we demonstrated that calpain activation produces a truncation of GSK-3. In this study, we show that calpain-mediated GSK-3 truncation, induced by N-methyl-D-aspartic acid (NMDA), depends on extracellular calcium. Primary cultures of cortical neurons treated with NMDA reduce GSK-3 levels up to 75%, although the truncated form of GSK-3 does not accumulate, suggesting that a short-lived product is formed. The data obtained with human AD samples suggest that, although a great variability exists at least in postmortem samples, truncated GSK-3 does not accumulate. However, memantine, a non-competitive NMDA receptor which has been approved for the treatment of moderate to severe AD, is able to inhibit GSK-3 truncation induced by NMDA in primary cultures of cortical neurons in a dose-dependent manner. Thus, memantine modulates GSK-3 signaling, which might explain its protective role in AD. Overall, our data reinforces the important relationship between NMDA receptors and GSK-3 and their involvement as one of the first steps in neurodegenerative diseases such as AD.
Tony Valente, Juan Hidalgo, Irene Bolea, Bartolomé Ramirez, Neus Anglés, Jordi Reguant, José Ramón Morelló, Cristina Gutiérrez, Mercè Boada, Mercedes Unzeta
A Diet Enriched in Polyphenols and Polyunsaturated Fatty Acids, LMN Diet, Induces Neurogenesis in the Subventricular Zone and Hippocampus of Adult Mouse Brain
Abstract: At present it is widely accepted that there are at least two neurogenic sites in the adult mammalian brain: the subventricular zone (SVZ) of lateral ventricles and the subgranular zone (SGZ) of the hippocampus dentate gyrus. The adult proliferation rate declines with aging and is altered in several neurodegenerative pathologies including Alzheimer’s disease. The aim of this work was to study whether a natural diet rich in polyphenols and polyunsaturated fatty acids (LMN diet) can modulate neurogenesis in adult mice and give insight into putative mechanisms. Results with BrdU and PCNA demonstrated that the LMN fed mice had more newly generated cells in the SVZ and SGZ, and those with DCX (undifferentiated neurons) and tyrosine hydroxylase, calretinin, and calbindin (differentiated neurons) immunostainings and western blots demonstrated a significant effect on neuronal populations, strongly supporting a positive role of the LMN diet on adult neurogenesis. In primary rat neuron cultures, the LMN cream dramatically protected against damage caused by both hydrogen peroxide and Aβ1-42, demonstrating a potent antioxidant effect that could play a major role in the normal adult neurogenesis and, moreover, the LMN diet could have a significant effect combating the cognitive function decline during both aging and neurodegenerative diseases such as Alzheimer’s disease.
Barbara Borroni, Mario Grassi, Silvana Archetti, Chiara Costanzi, Marta Bianchi, Luigi Caimi, Carlo Caltagirone, Monica Di Luca, Alessandro Padovani (Communicated by Valeria Drago)
BDNF Genetic Variations Increase the Risk of Alzheimer’s Disease-Related Depression
Abstract: The gene encoding the brain-derived neurotrophic factor (BDNF) has been demonstrated as a candidate for Alzheimer’s disease-related depression (AD-D) susceptibility. Additionally, an association between AD-D and the functional valine to methionine (Val66Met) polymorphism has been reported. The aim of this study was to assess the genetic contribution of other BDNF variants to AD-D. Two-hundred forty-five AD patients were divided into two subgroups according to the presence (AD-D) or the absence (AD-nD) of depressive symptoms. Four single-nucleotide polymorphisms within BDNF gene were considered, i.e., C270T, rs2049045 C/G, G196A (Val66Met), and G11757C. In our sample, 35.5% of patients (n=87) reported AD-related depressive symptoms. The individual SNP analysis showed an association between G196A and G11757C genotypes and AD-D. Accordingly, considering the allele frequencies, BDNF 196*A allele was significantly overrepresented in AD-D compared to AD-nD (OR=1.80, 95% CI=1.19-2.72), as well as BDNF 11757*C allele (OR=1.90, 95% CI=1.25-2.90). Haplotype analyses revealed that the alleles at four loci (C270T, rs2049045 C/G, G196A, G11757C) interacted to further increase the risk of AD-D. Compared to the most common not-at-risk C-C-G-G haplotype, C-G-A-C (OR=3.55, 95% CI=1.44-8.76, P=0.006) and C-C-A-C haplotypes (OR=1.72, 95% CI=1.03-2.87, P=0.037) were overrepresented in AD-D. This study suggests that BDNF genetic variations play a role in the susceptibility to AD-related depression.
Marta Tomàs, Neus Garcia, Manuel M. Santafé*, Maria Lanuza, Josep Tomàs* *These authors contributed equally to this work.
Protein Kinase C Involvement in the Acetylcholine Release Reduction Induced by Amyloid-β25-35 Aggregates on Neuromuscular Synapses
Abstract: Using intracellular recording of the diaphragm muscle of adult rats, we have investigated the short-term functional effects of amyloid-β (Aβ)25-35 peptide aggregates in the modulation of acetylcholine (ACh) release and the involvement of protein kinase C (PKC). The non-aggregated form of this peptide does not change the evoked and spontaneous transmitter release parameters on the neuromuscular synapse. However, the aggregated form of Aβ25-35 acutely interferes with evoked quantal ACh release (~40% reduction) when synaptic activity in the ex vivo neuromuscular preparation is maintained by low frequency (1 Hz) electrical stimulation. This effect is partially dependent on the activity of PKC that may have a permissive action. The end result of Aβ25-35 is in opposition to the PKC-dependent maintenance effect on ACh release manifested in active synapses.
Scott E. Counts, Bin He, Shaoli Che, Stephen D. Ginsberg, Elliott J. Mufson
Galanin Fiber Hyperinnervation Preserves Neuroprotective Gene Expression in Cholinergic Basal Forebrain Neurons in Alzheimer’s Disease
Abstract: Fibers containing galanin (GAL) hyperinnervate cholinergic basal forebrain nucleus basalis neurons in late stage Alzheimer’s disease (AD), yet the molecular consequences of this phenomenon are unknown. To determine whether GAL alters the expression of genes critical to cholinergic basal forebrain cell survival in AD, single cell microarray analysis was used to determine mRNA levels within nucleus basalis neurons lacking GAL innervation from subjects who died with a clinical diagnosis of no cognitive impairment (NCI) compared to nucleus basalis neurons from AD cases either lacking GAL hyperinnervation (AD/GAL-) or those displaying prominent GAL hyperinnervation (AD/GAL+). Levels of mRNAs encoding putatively neuroprotective proteins such as the GluR2 Ca2+-impermeable glutamate receptor subunit, superoxide dismutase 2, and the GLUT2 glucose transporter were significantly decreased in AD/GAL- nucleus basalis neurons compared to NCI and AD/GAL+ neurons. By contrast, mRNAs encoding calpain catalytic and regulatory subunits, which may contribute to cell death in AD, were increased in AD/GAL- compared to NCI and AD/GAL+ neurons. Hence, GAL fiber hyperinnervation appears to preserve the expression of genes subserving multiple neuroprotective pathways suggesting that GAL overexpression regulates cholinergic basal forebrain neuron survival in AD.
Andrej Kovac, Monika Zilkova, Maria A. Deli, Norbert Zilka and Michal Novak
Human Truncated Tau is Using a Different Mechanism from Amyloid-β to Damage the Blood-Brain Barrier
Abstract: Recent findings showed that vascular dysfunction is considered to be an integral part of Alzheimer’s disease pathology. Increased microvascular permeability is mainly associated with cerebrovascular amyloid-β deposits. In contrast, little is known about the relationship between functional impairment of the blood-brain barrier and misfolded tau. In the present study, we examined whether human truncated tau is able to impair blood-brain barrier in an in vitro model. We have found that truncated tau induced a very strong polarity-dependent effect in the rat blood-brain barrier model. When the tau was added to the upper compartment of the model containing endothelial cells (apical treatment), no effect was observed. However, the application of tau to the lower compartment (basolateral treatment), consisting of astroglia-microglia culture, triggered significant decrease of transendothelial electrical resistance and increase of endothelial permeability for mannitol. Further, we found that truncated tau showed cytotoxic effects on astroglia-microglia culture manifested by increased extracellular adenylate kinase levels. Molecular analysis of underlying mechanisms of tau induced blood-brain barrier damage revealed the contribution of pro-inflammatory cytokine tumor necrosis factor-α and chemokine MCP-1 released from activated microglial cells. This study for the first time uncovers novel toxic gain of function of misfolded tau that could contribute to the cerebral microvascular damage in human tauopathies.
Yuh-Te Lin, Jiin-Tsuey Cheng, Yun-Chin Yao, Liang-I Juo, Yuk-Keung Lo, Ching-Hwung Lin, Luo-Ping Ger, Pei-Jung Lu
Increased Total Tau But Not Amyloid-β42 in Cerebrospinal Fluid Correlates with Short-Term Memory Impairment in Alzheimer’s Disease
Abstract: Given the need for tools for early and accurate diagnosis, prediction of disease progression, and monitoring efficacy of therapeutic agents for AD, the study of cerebrospinal fluid (CSF) biomarkers has become a rapidly growing field of research. Several studies have reported conflicting data regarding the relationships between CSF biomarkers and dementia severity. In this study, we have focused on the identification of CSF biomarkers and their correlations with the impairment of different cognitive domains measured using the Cognitive Abilities Screening Instrument (CASI). Patients with AD (n=28), non-AD dementia (n=16), other neurological disorders (OND, n=14), and healthy controls (HC, n=21) were enrolled. Our results revealed significantly higher CSF total tau (t-tau) and lower amyloid-β42 levels in AD patients compared with those in HC and OND groups. Moreover, our data show that CSF t-tau levels, but not Aβ42 levels, have an inverse correlation with the score of short-term memory in CASI for patients with AD (Spearman: r=-0.444; p=0.018). This data might indicate that the higher CSF t-tau level is associated with more NFT pathology and more severe impairment of short-term memory in AD patients.
Victoria Campos-Peña, José Tapia-Ramírez, Carmen Sánchez-Torres, Marco Antonio Meraz-Rios
Pathological-Like Assembly of tau Induced by a Paired Helical Filament Core Expressed at the Plasma Membrane
Abstract: The hallmark of Alzheimer’s disease is the pathological aggregation of tau proteins into paired helical filaments and neurofibrillary tangles. This paper evaluates the abnormal expression and localization of chimeric tau molecules at the plasma membrane of COS-7 cells and its relationship with tau polymerization. Overexpression of these proteins, in combination with either tau441 or tau391, induces tau to assemble into β-pleated sheets that are recognized by Thiazin red. Immunoelectromicroscopy analysis revealed the presence of filaments close to the plasma membrane resembling those found in Alzheimer’s disease. The capacity of plasma membrane-associated chimeric tau proteins to capture full length tau was increased in the presence of H2O2 or okadaic acid treatments. This suggests that hyperphosphorylation or an oxidative environment could both influence the biochemical properties of the cell that lead to assembly of paired helical filaments. The altered localization of tau protein at the plasma membrane could play a key role in the assembly of pathological tau.
AnnaMaria Cimini, Sandra Moreno, Marcello D’Amelio, Loredana Cristiano, Barbara D’Angelo, Stefano Falone, Elisabetta Benedetti, Paolo Carrara, Francesca Fanelli, Francesco Cecconi, Fernanda Amicarelli, Maria Paola Cerù *These authors contributed to the present work equally.
Early Biochemical and Morphological Modifications in the Brain of a Transgenic Mouse Model of Alzheimer’s Disease: A Role for Peroxisomes
Abstract: The central role of peroxisomes in reactive oxygen species and lipid metabolism and their importance in brain functioning are well established. The aim of this work has been to study the peroxisomal population in the Tg2576 mouse model of Alzheimer’s disease (AD), at the age of three months when no apparent signs of behavioral, neuroanatomical, cytological, or biochemical alterations have been so far described. The expression and localization of peroxisomal (PMP70, CAT, AOX, and THL) and peroxisome-related proteins (PEX5p, GPX1, SOD1, and SOD2) were studied in the neocortex and hippocampus of transgenic and wild-type animals. Oxidative stress markers (TBARS, acrolein, and 8-OHG) were also evaluated. Our results demonstrate that significant alterations are already detectable at this early stage of the disease and also involve peroxisomes. Their number and protein composition change concomitantly with early oxidative stress. Interestingly, the neocortex shows a compensatory response, consisting in an increase of reactive oxygen species scavenging enzymes, while the hippocampus appears more prone to the oxidative insult. This different behavior could be related to metabolic differences in the two brain areas, also involving peroxisome abundance and/or enzymatic content.
Emilio Di Maria, Cristian Bonvicini, Cristina Bonomini, Antonella Alberici, Orazio Zanetti, Massimo Gennarelli (Communicated by Alessandro Serretti)
Genetic Variation in the G72/G30 Gene Locus (DAOA) Influences the Occurrence of Psychotic Symptoms in Patients with Alzheimer’s Disease
Abstract: The occurrence of neuropsychiatric symptoms in patients with Alzheimer’s disease hampers the clinical management and exacerbates the burden for caregivers. To what extent psychotic symptoms are genetically determined and which are the genes involved has to be established. We tested the hypothesis that the occurrence of delusions and hallucinations in AD is associated with variations in the G72/DAOA gene, which is supposed to play a key role in the glutamate pathway regulated through the NMDA receptors. A panel of single nucleotide polymorphisms were genotyped in a cohort of 185 Alzheimer’s disease patients. The analysis demonstrated a nominally significant association (p<0.05) with one single nucleotide polymorphisms (rs2153674). In addition, multivariate regression showed that the rs2153674 genotype accounts for up to 15% of the variance in delusions severity, as assessed by using the Neuropsychiatric Inventory. If the results from the present study will be replicated, the glutamate hypothesis could be invoked to explain the occurrence of psychosis in neurodegenerative disorders.
Allal Boutajangout, Fernando Goni, Elin Knudsen, Fernanda Schreiber, Ayodeji Asuni, David Quartermain, Blas Frangione, Alejandro Chabalgoity, Thomas Wisniewski, Einar M. Sigurdsson *Contributed equally to the project
Diminished Amyloid-β Burden in Tg2576 Mice Following a Prophylactic Oral Immunization with a Salmonella-Based Amyloid-β Derivative Vaccine
Abstract: Immunotherapy holds great promise for Alzheimer’s disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. Prior to the side effects in the first Elan/Wyeth AD vaccine trial, we proposed using amyloid-β (Aβ) derivatives as a safer approach. The route of administration may also affect vaccine safety. To assess the feasibility of oral immunization that promotes mucosal immunity, Tg2576 AD model mice were treated prophylactically three times over 6 weeks starting at 3-5 months of age with a Salmonella vaccine expressing K6Aβ1-30. At 22-24 months of age, cortical Aβ plaque burden and total Aβ40/42 levels were reduced by 48-75% in the immunized mice compared to controls, which received unmodified Salmonella. Plaque clearance was not associated with increased microglial activation which may be explained by the long treatment period. Furthermore, cerebral microhemorrhages were not increased in the treated mice in contrast to several passive Aβ antibody studies. These results further support our findings with this immunogen delivered subcutaneously and demonstrate its efficacy when given orally which may provide added benefits for human use.
Meeting Report from the Alzheimer Research Forum
12th International Conference on Alzheimer's Disease (ICAD), Vienna, Austria
Book Review: Current Hypotheses and Research Milestones in Alzheimer’s Disease. Ricardo Maccioni and George Perry (eds). Springer Science-Business Media, 2009. Reviewed by Athena Andreadis.