| Volume
26, Number 3, September 2011
Pages 413-430
Review
Petr Novak, Michal Prcina, Eva Kontsekova
Tauons and Prions: Infamous Cousins?
Abstract: The paradigm of Alzheimer’s disease (AD) is one subject to frequent change: what was thought to be a rare form of pre-senile dementia was revealed as a wide-spread malady; where amyloid-β was deemed the sole causative agent for the better part of 20 years, tau protein was shown to play a crucial role in AD genesis. With the discovery of possible prion-like phenomena in this disease supposedly driven by cell-autonomous processes, an evaluation of the similarities and differences between tau-driven neurodegeneration and prion disease becomes necessary. In this article, we provide a comparison of the template agent genesis, filament assembly, as well as intra- and inter-individual spread of prions and tauons.
Pages 431-439
Louisa Goumidi, Karin Dahlman-Wright, Isabel Tapia-Paez, Hans Matsson, Florence Pasquier, Philippe Amouyel, Juha Kere, Jean-Charles Lambert, Aline Meirhaeghe (Handling Associate Editor: Daniela Galimberti)
Study of Estrogen Receptor-α and Receptor-β Gene Polymorphisms on Alzheimer’s Disease
Abstract: Estrogen treatment can modulate the risk for developing dementia in women. Therefore, single nucleotide polymorphisms (SNPs) in the estrogen receptor genes may constitute genetic susceptibility factors to Alzheimer’s disease (AD). Thus, we investigated the impact of the genetic variability of the estrogen receptor α 1 (ESR1) and estrogen receptor α 2 (ESR2) genes on late onset AD risk. We analyzed 39 SNPs in ESR1 and 5SNPs in ESR2 in a French case-control study of sporadic AD (1007 cases/647 controls). Individuals carrying the minor allele of rs7450824 had a lower risk of AD than homozygous subjects for the major allele (age, gender, and APOE e4 allele adjusted odds ratio=0.71 [0.57-0.89], p=0.003). However, this association did not resist Bonferroni correction for multiple testing (p-threshold<0.001). Consistently, no significant association could be detected when considering age of onset. We also tested for possible interactions between the ESR SNPs and APOE status (e4 allele) or gender but no significant interaction could be observed. Even after stratifying the sample on APOE status or gender, no significant association with AD risk could be detected. Finally, we searched for potential gene-gene interactions between ESR1 and ESR2 SNPs but no significant interaction could be detected. Our results reinforce the notion that SNPs in the ESR1 or ESR2 genes do not seem to play a major role in the genetic susceptibility of AD.
Supplementary Data for Goumidi et al. article (PDF)
Pages 441-445
Davide Vacirca, Cristiana Barbati, Beatrice Scazzocchio, Roberta Masella, Giuseppe Rosano, Walter Malorni, Elena Ortona
Anti-ATP Synthase Autoantibodies from Patients with Alzheimer’s Disease Reduce Extracellular HDL Level
Abstract: Aside from being an integral protein involved in the synthesis and hydrolysis of ATP, Ecto-F1-ATPase plays a role in cholesterol homeostasis. We demonstrated the presence of autoantibodies to ecto-F1-ATPase (ASabs) in sera and cerebrospinal fluids from patients with Alzheimer’s disease (AD). Herein we show that ASabs, unlike irrelevant antibodies, can increase cellular uptake of HDL, a risk factor for the development of AD, via a mechanism involving the prototypical function of ecto-F1-ATPase: the generation of ADP due to the hydrolysis of ATP. Piceatannol, a specific inhibitor ecto-F1-ATPase, completely hindered these effects. We hypothesize that ASabs could exert a pathogenetic role in AD.
Pages 447-455
Paramita Mookherjee, Pattie S. Green, G. Stennis Watson, Marcos A. Marques, Kohichi Tanaka, Kole D. Meeker, James S. Meabon, Ning Li, Ping Zhu, Valerie G. Olson, David G. Cook
GLT-1 Loss Accelerates Cognitive Deficit Onset in an Alzheimer’s Disease Animal Model
Abstract: Glutamate transporters regulate normal synaptic network interactions and prevent neurotoxicity by rapidly clearing extracellular glutamate. GLT-1, the dominant glutamate transporter in the cerebral cortex and hippocampus, is significantly reduced in Alzheimer’s disease (AD). However, the role GLT-1 loss plays in the cognitive dysfunction and pathology of AD is unknown. To determine the significance of GLT-1 dysfunction on AD-related pathological processes, mice lacking one allele for GLT-1(+/-) were crossed with transgenic mice expressing mutations of the amyloid-β protein precursor and presenilin-1 (AβPPswe/PS1DE9) and investigated at 6 or 9 months of age. Partial loss of GLT-1 unmasked spatial memory deficits in 6-month-old mice expressing AβPPswe/PS1ΔE9, with these mice also exhibiting an increase in the ratio of detergent-insoluble Aβ42/Aβ40. At 9 months both behavioral performance and insoluble Aβ42/Aβ40 ratios among GLT-1(+/+)/AβPPswe/PS1ΔE9 and GLT-1(+/-)/AβPPswe/PS1ΔE9 mice were comparable. These results suggest that deficits in glutamate transporter function compound the effects of familial AD AβPP/PS1 mutant transgenes in younger animals and thus may contribute to early occurring pathogenic processes associated with AD.
Pages 457-466
Karine Madsen, Wolf-Julian Neumann, Klaus Holst, Lisbeth Marner, Mette Thorlund Haahr, Szabolcs Lehel, Gitte Moos Knudsen, Steen Gregers Hasselbalch (Handling Associate Editor: Joaquin Del Rio)
Cerebral Serotonin 4 Receptors and Amyloid-β in Early Alzheimer’s Disease
Abstract: The 5-HT4 receptor may play a role in memory and learning and 5-HT4 receptor activation has been suggested to modulate acetylcholine release and to reduce amyloid-β (Aβ) accumulation. The aim of this study was for the first time to investigate the in vivo cerebral 5-HT4 receptor binding in early Alzheimer disease (AD) patients in relation to cortical Aβ burden. Eleven newly diagnosed untreated AD patients (mean MMSE 24, range 19-27) and twelve age- and gender-matched healthy controls underwent a two-hour dynamic [11C]SB207145 PET scan to measure the binding potential of the 5-HT4 receptor. All AD patients and eight healthy controls additionally underwent a [11C]PIB PET scan to measure the cortical Aβ burden. When AD patients were defined on clinical criteria, no difference in cerebral 5-HT4 receptor binding between AD patients and healthy controls was found (p=0.54). However, when individuals were reassigned to groups according to their amyloid status, the PIB-positive individuals had 13% higher 5-HT4 receptor levels than PIB-negative individuals (p=0.02) and the importance of classification of groups is emphasized. The 5-HT4 receptor binding was a positively correlated to Aβ burden (p=0.03) and negatively to MMSE score of the AD patients (p=0.02). Our data suggests that cerebral 5-HT4 receptor upregulation starts at a preclinical stage of and continues while dementia is still at a mild stage, which contrasts other receptor subtypes. We speculate that this may either be a compensatory effect of decreased levels of interstitial 5-HT, an attempt to improve cognitive function, increase acetylcholine release or to counteract Aβ accumulation.
Pages 467-476
Ricardo Quiroz-Baez, Patricia Ferrera, Rigoberto Rosendo-Gutiérrez, Julio Morán, Federico Bermúdez-Rattoni, Clorinda Arias
Caspase-12 Activation is Involved in Amyloid-β Protein-Induced Synaptic Toxicity
Abstract: Synapse loss is considered to be the best correlate of cognitive impairments in Alzheimer’s disease (AD), and growing evidence supports the notion that certain events that trigger neuronal death in AD can be initiated by the local activation of caspases within the synaptic compartment. We have demonstrated previously that presynaptic terminals are particularly vulnerable to endoplasmic-reticulum (ER)-stress depending of amyloid-β protein (Aβ). This toxicity included a notable reduction of actin and synaptophysin protein and mitochondrial dysfunction. This synaptic damage was prevented by incubation with a wide range of caspase inhibitor, suggesting the activation of local synaptic apoptotic mechanisms. The ER-resident caspase-12 was initially identified as a mediator of Aβ neurotoxicity. Thus, the current study was conducted to explore the presence and local activation of the caspase-12 in cortical and hippocampal synaptosomes isolated from rat and from the triple transgenic mouse model of AD (3xTg-AD) in the presence of Aβ and ryanodine. Under these conditions, we found mitochondrial failure accompanied by a reduction in actin levels which was dependent on caspase-12 activation suggesting its participation in Aβ-induced synaptic toxicity.
Pages 477-484
Mark S. Stein, Samuel C. Scherer, Kylie S. Ladd, Leonard C. Harrison
A Randomized Controlled Trial of High-Dose Vitamin D2 Followed by Intranasal Insulin in Alzheimer’s Disease
Abstract: A diet lacking vitamin D is linked with dementia, but vitamin D has not been tested in a randomized controlled trial (RCT) in Alzheimer’s disease (AD). Nasal insulin acutely improves cognition and vitamin D upregulates insulin receptor expression and enhances insulin action. In an RCT we examined the effect of high-dose vitamin D followed by nasal insulin on memory and disability in mild-moderate AD. 63 community-dwelling individuals aged >60 were recruited; 32 with mild-moderate disease (Folstein Mini-Mental State Examination [MMSE] score 12-24) met entry criteria and were randomized. All took low-dose vitamin D (1000IU/day) throughout. After run-in (8 weeks), they were randomized to additional high-dose D/placebo for 8 weeks, followed immediately by randomization to nasal insulin (60 IU qid)/placebo for 48 h. Primary outcome measures were Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) and Disability Assessment in Dementia (after high-dose D) and ADAS-cog and Wechsler Memory Scale-Revised Logical memory (WMS-R LM) for immediate and delayed recall (after nasal insulin). Baseline median (interquartile range, IR) age, MMSE, and ADAS-cog were 77.5 (69-80), 19.5 (17-22), and 25.5 (20-31), respectively. Median 25OHD increased from 49 to 60 nM (p<0.01) after run-in and was 187 nM after high-dose vitamin D and 72 nM after placebo (p<0.001). Neither cognition nor disability changed significantly after high-dose D. ADAS-cog improved by a median (IR) of 9 (1-11) with nasal insulin after placebo high-dose vitamin D (p=0.02), but may represent regression to the mean as WLS-R LM did not change. We conclude that high-dose vitamin D provides no benefit for cognition or disability over low-dose vitamin D in mild-moderate AD.
Pages 485-494
Francis Hane, Elizabeth Drolle, Ravi Gaikwad, Erin Faught, Zoya Leonenko (Handling Associate Editor: Jose Jimenez)
Amyloid-β Aggregation on Model Lipid Membranes: An Atomic Force Microscopy Study
Abstract: Amyloid fibril formation is generally associated with many neurodegenerative disorders, Alzheimer’s disease (AD) being one of them. Although fibril plaque formation is associated with biological membranes in vivo, the role of the cell surfaces in amyloid fibril formation and molecular mechanism of amyloid toxicity are not well understood. Understanding the details of amyloid interaction with lipid membrane may shed light on the mechanism of amyloid toxicity. Using atomic force microscopy, we investigated aggregation of amyloid-β1-42 (Aβ1-42) on model phospholipid membranes as a function of time and membrane composition. Neutral, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), anionic - 1,2-dioleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (sodium salt) (DOPG), and cationic - 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), were used to study the effect of lipid type on amyloid binding. We showed that both the charge on the lipid head group and lipid phase affect the interaction of amyloid oligomers with the membrane surface changing the rate of adsorption and causing changes in membrane structure and structure of amyloid deposits. We observed that well resolved by AFM amyloid aggregates progressively accumulate in a similar manner on the surface of neutral DPPC gel phase membrane and on the surface of fluid phase negatively charged DOPG membrane. Positively charged fluid DOTAP membrane behaved similarly to neutral fluid phase DOPC membrane showing small oligomers with reduced height on the surface of the membrane, fusing into the lipid membrane surface. We showed that both the charge on the lipid head group and lipid phase affect the interaction of amyloid oligomers with the membrane surface changing the rate of adsorption and causing changes in membrane structure and structure of amyloid deposits. We observed that well resolved amyloid aggregates progressively accumulate in a similar manner on the surface of neutral DPPC gel phase membrane and on the surface of fluid phase negatively charged DOPG membrane. In contrast to DPPC and DOPG, positively charged fluid DOTAP membrane and neutral fluid phase DOPC membrane contain amyloid deposits with reduced height, which suggests fusing of Aβ1-42 into the lipid membrane surface.
Supplementary Data for Hane et al. article (PDF)
Pages 495-505
Whitney Wharton, Laura D. Baker, Carey E. Gleason, Maritza Dowling, Jodi H. Barnet, Sterling Johnson, Cynthia Carlsson, Suzanne Craft, Sanjay Asthana (Handling Associate Editor: Mary Tierney)
Short-term Hormone Therapy with Transdermal Estradiol Improves Cognition for Postmenopausal Women with Alzheimer's Disease: Results of a Randomized Controlled Trial
Abstract: We aimed to conduct a placebo-controlled, double-blind, parallel-group design intervention study to evaluate the therapeutic efficacy of hormone therapy (HT) in postmenopausal women with mild to moderate Alzheimer’s disease (AD).
The trial was designed to evaluate the dose-dependent effects of transdermal 17-β estradiol, unopposed and opposed with medroxyprogesterone (MPA, Provera©), for 12 months in 50 postmenopausal women with AD. Participants were assessed using cognitive measures at baseline, months 1, 3, 6, and 12 of treatment and eight weeks post treatment (month 15). The dropout rate was 49% across 12 months. As a result, of the Women’s Health Initiative (WHI) and anticipated increased attrition, the protocol was modified to examine data only at time points where attrition was less than 30%. The results of sensitivity analyses indicated robust and reliable data collected in the first three months of the trial. Data collected in the first three months of the trial for forty-three participants were analyzed. HT had favorable cognitive effects across multiple cognitive domains, including visual memory (p-values <0.030) and semantic memory (p-values <0.037) in postmenopausal women with AD. Moreover, treatment-related changes in plasma estradiol were positively correlated with improvements in visual memory. Short-term HT that includes the use of estradiol has favorable effects on cognition in women with AD.
Pages 507-521
Natasa Dragicevic, Adam Smith, Xiaoyang Lin, Fang Yuan, Neil Copes, Vedad Delic, Jun Tan, Chuanhai Cao, R Douglas Shytle, Patrick C Bradshaw (Handling Associate Editor: Russell Swerdlow)
Green Tea Epigallocatechin-3-Gallate (EGCG) and Other Flavonoids Reduce Alzheimer’s Amyloid-Induced Mitochondrial Dysfunction
Abstract: Amyloid-β (Aβ)-induced mitochondrial dysfunction may play a role in the onset and progression of Alzheimer’s disease (AD). Therefore, therapeutics targeted to improve mitochondrial function could be beneficial. Plant-derived flavonoids have shown promise in improving certain AD phenotypes, but the overall mechanism of action(s) through which flavonoids protect from AD is still unknown. To identify flavonoids and other natural products that may correct amyloid-induced mitochondrial dysfunction, 25 natural products were screened for their ability to restore altered mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, or ATP levels in neuroblastoma cells expressing mutant amyloid-β protein precursor (AβPP). Epigallocatechin-3-gallate (EGCG) and luteolin were identified as the top two mitochondrial restorative compounds from the in vitro screen. EGCG was further tested in vivo to determine its effects on brain mitochondrial function in an AβPP/PS-1 (presenilin 1) double mutant transgenic mouse model of AD. EGCG treatment restored mitochondrial respiratory rates, MMP, ROS production, and ATP levels by 50 to 85% in mitochondria isolated from the hippocampus, cortex, and striatum. The results of this study lend further credence to the notion that EGCG and other flavonoids, such as luteolin, are ‘multipotent therapeutic agents’ that not only reduce toxic levels of brain Aβ, but also hold the potential to protect neuronal mitochondrial function in AD.
Pages 523-530
Lu Zhang, Yu Fang, Zhaoshu Zeng, Yajun Lian, Jianke Wei, Hongcan Zhu, Yanjie Jia, Xinyu Zhao, Yuming Xu (Handling Associate Editor: Israel Ampuero)
BDNF Gene Polymorphisms are Associated with Alzheimer's Disease-Related Depression and Antidepressant Response
Abstract: Brain-derived neurotrophic factor (BDNF) is needed to support neuronal survival and differentiation. It also promotes synaptic remodeling and modulates the function of many other neurotransmitters. The current study examined potential association between single nucleotide polymorphisms (SNPs) of the BDNF gene (G11757C, C270T, G196A, G-712A) and Alzheimer's disease-related depression (AD-D). Participants included 336 patients with AD; 128 of these patients had AD-D. Response to 8-week paroxetine treatment was also assessed. The frequency of the 11757C allele was significantly higher in AD-D than in the Alzheimer's disease without depression (AD-nD) patients (p=0.003 after Bonferroni correction). The 196A allele occurred with significantly higher frequency in AD-D patients (p=0.001 after Bonferroni correction versus AD-nD). Carriers of the A allele of G196A responded better to paroxetine treatment. These findings support an important role of BDNF polymorphism in AD-D.
Pages 531-541
D Richard Lachno, Martin J Romeo, Eric R Siemers, Hugo Vanderstichele, Els Coart, Robert J Konrad, Joseph J Zajac, Jayne A Talbot, Hans F Jensen, Gopalan Sethuraman, Ronald B DeMattos, Patrick C May, Robert A Dean(Handling Associate Editor: Henrik Zetterberg)
Validation of ELISA Methods for Quantification of Total Tau and Phosporylated-Tau181 in Human Cerebrospinal Fluid with Measurement in Specimens from Two Alzheimer’s Disease Studies.
Abstract: Tau measurements in cerebrospinal fluid (CSF) are gaining acceptance as aids to diagnosis of Alzheimer’s disease (AD) and differentiation from other dementias. Two ELISA assays, the INNOTEST® hTAU Ag and the INNOTEST® PHOSPHO-TAU(181P) for quantification of t-tau and p-tau181 respectively, have been validated to regulatory standards. Validation parameters were determined by repeated testing of human CSF pools. Specimens from Phase II studies of the γ-secretase inhibitor semagacestat and the therapeutic antibody solanezumab at baseline and following 12-14 weeks of treatment were also tested. Estimated intra-assay CV for repeated testing of 3 CSF pools were ≤ 11.5% and RE varied between −14.1% and +6.4% . Inter-assay CV for t-tau was < 5% and RE was within ± 8%. For p-tau181, inter-assay CV was < 9% and RE was within ± 2.5%. Total CV (intra-assay plus inter-assay) were below 10% for both analytes. Up to 20-fold dilutional linearity was demonstrated for both analytes. Stability of t-tau and p-tau181 was demonstrated in CSF during five freeze-thaw cycles at ≤ −20°C and ≤ −70°C and at 18–22°C for up to 24 h. Neither semagacestat nor solanezumab interfered with either assay. Inter-individual t-tau and p-tau181 concentrations were highly variable but intra-individual variations were small. These assays are suitable for analysis of CSF t-tau and p-tau181 in a single laboratory supporting multi-center AD clinical trials. No effect of treatment with semagacestat or solanezumab was observed in response to three months of drug administration.
Supplementary Data for Lachno et al. article (PDF)
Pages 543-551
Alberto Villarejo, Julián Benito-León, Rocío Trincado, Ignacio J. Posada, Verónica Puertas-Martín, Raquel Boix, Mª José Medrano, Félix Bermejo-Pareja
Dementia-Associated Mortality at Thirteen Years in the NEDICES Cohort Study
Abstract: To evaluate the mortality, thirteen years after the baseline wave (1994), of participants suffering dementia in the Neurological Disorders in Central Spain (NEDICES) Cohort Study, we conducted a population-based cohort study in the elderly (65 years and more) with 5,278 screened participants at baseline. Mortality has been evaluated by means of the National Death Registry of Spain at 1-5-2007, 13 years after enrolment. Cox’s proportional hazards regression models were used to evaluate the hazard of death according to dementia severity and type, adjusting for potential covariates (gender, age, level of education, and co-morbidity). Survival was estimated using Kaplan-Meier method.Of the 5,278 participants screened at baseline, 306 had dementia. Mortality at 13 years was: 275 deaths (89.9%) in dementia subjects; and 2,426 (49.0%) in subjects without dementia. Mortality was higher and statistically significant in dementia subjects. The degree of dementia (DSM-III-R) correlated with the risk of mortality, from mild (HR= 2.23; CI: 1.77-2.82) to moderate (HR=3.10; CI: 2.47-3.89) and severe dementia (HR= 4.98; CI: 3.85-6.44).Survival was similar in Alzheimer’s disease and vascular dementia. Factors associated with higher mortality in Cox proportional hazard models were older age, male gender, and comorbidity. Using Population Attributable risk (PAR%), dementia was related to 11.3% of all deaths. Dementia intensity increases the mortality risk at ten years in the NEDICES Study as in other cohort studies. Age, gender, and co-morbidity are associated with higher mortality in dementia patients. Almost one third of deaths in persons over 85 years-old could be attributable to dementia.
Pages 553-563
Audrey Gabelle, Stéphane Roche, Christian Gény, Karim Bennys, Pierre Labauge, Yannick Tholance, Isabelle Quadrio, Laurent Tiers, Baptiste Gor, Justine Boulanghien, Chloé Chaulet, Alain Vighetto, Bernard Croisile, Pierre Krolak-Salmon, Armand Perret-Liaudet, Jacques Touchon, Sylvain Lehmann
Decreased sAβPPβ, Aβ38, and Aβ40 Cerebrospinal Fluid Levels in Frontotemporal Dementia
Abstract: To improve the etiological diagnosis of neurodegenerative dementias like Alzheimer’s disease (AD) or frontotemporal dementia (FTD), we evaluated the value of individual and combined measurements of the following relevant cerebrospinal fluid (CSF) biomarkers: Tau, 181 p-Tau, Aβ38, Aβ40, Aβ42, sAβPPα, and sAβPPβ. This study conducted in two centers included patients with FTD (n=34), AD (n=52), as well as a control group of persons without dementia (CTRL, n=42). Identical clinical criteria and pre-analytical conditions were used while CSF biomarkers were measured using commercial single and multiplex quantitative immunoassays. Thorough statistical analyses, including ROC curves, logistic regressions, and decision trees, were performed. We validated in AD the specific increase of p-Tau levels and the decrease of Aβ42 levels, two biological hallmarks of this disease. Tau concentrations were highest in AD and intermediate in FTD when compared to CTRL. The most interesting results were obtained by focusing on amyloid biomarkers as we found out in FTD a significant decrease of sAβPPβ, Aβ38, and Aβ40 levels. Aβ38 in particular was the most useful biomarker to differentiate FTD subjects from the CTRL population. Combining p-Tau and Aβ38 led us to correctly classifying FTD patients with sensitivity at 85% and specificity at 82%. Significant changes in amyloid biomarkers, particularly for Aβ38, are therefore seen in FTD. This could be quite useful for diagnosis purposes and it might provide additional evidence on the interrelationship between Tau and AβPP biology which understanding is essential to progress towards optimal therapeutic and diagnostic approaches of dementia.
Pages 565-581
Diana FF Silva, A Raquel Esteves, Daniela M Arduino, Catarina R Oliveira, Sandra M Cardoso
Amyloid-β-Induced Mitochondrial Dysfunction Impairs the Autophagic Lysosomal Pathway in a Tubulin Dependent Pathway
Abstract: Mitochondrial dysfunction is observed in Alzheimer's disease (AD) brain and peripheral tissues. Amyloid-β (Aβ) peptides are known to interact with several proteins inside the mitochondria, leading to mitochondrial dysfunction. Recent studies have provided substantial evidence that mitochondria serve as direct targets for Aβ-mediated neuronal toxicity. The observations that Aβ progressively accumulates in cortical mitochondria from AD patients and transgenic AD type mouse models suggest the role of mitochondrial Aβ in the pathogenesis or development of AD. Herein, we studied the downstream signaling pathways induced by A-mediated mitochondrial metabolism alterations and its consequences on cellular fate. We found that Aβ peptides induced an increase in NAD+ levels and a decrease in ATP levels, which was related with decreases in acetylated tubulin levels and tau hyperphosphorylation. As a result of microtubule disruption, alterations in macroautophagy, like a decrease in autophagossome degradation and altered cellular distribution of LC3B, were found. Taxol, a microtubule stabilizer drug, was able to restore microtubule network and to prevent cell death induced by Aβ peptides. Our data shows for the first time that mitochondrial and cytosolic Aβ oligomers were significantly reduced upon microtubule dynamics re-establishment. These observations point out that an intervention at a microtubule level may be effective as a disease modifying therapy.
Supplementary Data for Silva et al. article (PDF)
Pages 583-590
Gabriella Marcon*, Giacomina Rossi*, Giorgio Giaccone, Anna Rita Giovagnoli, Elena Piccoli, Sergio Zanini, Onelio Geatti, Vito Toso, Marina Grisoli, Fabrizio Tagliavini (Handling Associate Editor: Daniela Galimberti) *These authors contributed equally to the study
Variability of the Clinical Phenotype in an Italian Family with Dementia Associated with an Intronic Deletion in the GRN Gene
Abstract: Mutations in the progranulin gene (GRN) were recently identified as important cause of familial frontotemporal dementia (FTD). More than 60 pathogenic mutations have been reported up to now and prominent phenotypic variability within and among affected kindreds has been described. We have studied an Italian family with clinical evidence of dementia, and here we report detailed clinical records, imaging, sequential neurological examinations, cognitive assessments, and genetic analysis of three affected members of the same generation. Genetic analysis revealed the presence of the null mutation IVS6+5_8delGTGA in GRN, leading to haploinsufficiency, as documented by mRNA analysis. The mutation is associated with wide variation of the clinical phenotype, ranging from FTD to Alzheimer’s disease and to a rapidly-progressive dementia. In summary, the patients of this kindred showed highly variable clinical features that do not closely correspond to a pattern of the cerebral atrophy. Our data extend the phenotypic spectrum and the complexity of neurodegenerative diseases linked to GRN mutations.
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