Journal of Alzheimer's Disease - Volume 26, issue 3

Authors: Novak, Petr | Prcina, Michal | Kontsekova, Eva

Article Type: Review Article

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. Show more

Keywords: Alzheimer's disease, prions, tauons, tauopathies, truncated tau protein

DOI: 10.3233/JAD-2011-110194

Citation: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 413-430, 2011

Authors: Goumidi, Louisa | Dahlman-Wright, Karin | Tapia-Paez, Isabel | Matsson, Hans | Pasquier, Florence | Amouyel, Philippe | Kere, Juha | Lambert, Jean-Charles | Meirhaeghe, Aline

Article Type: Research Article

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 5 SNPs 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 ε4 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 (ε4 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. Show more

Keywords: Alzheimer's disease, association study, ESR, estrogens, estrogen receptor, polymorphism

DOI: 10.3233/JAD-2011-110362

Citation: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 431-439, 2011

Authors: Vacirca, Davide | Barbati, Cristiana | Scazzocchio, Beatrice | Masella, Roberta | Rosano, Giuseppe | Malorni, Walter | Ortona, Elena

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, ATP synthase, autoantibodies, HDL, piceatannol

DOI: 10.3233/JAD-2011-110350

Citation: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 441-445, 2011

Authors: Mookherjee, Paramita | Green, Pattie S. | Watson, G. Stennis | Marques, Marcos A. | Tanaka, Kohichi | Meeker, Kole D. | Meabon, James S. | Li, Ning | Zhu, Ping | Olson, Valerie G. | Cook, David G.

Article Type: Research Article

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/PS1ΔE9) 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. Show more

Keywords: Amyloid-β, dementia, excitatory, excitotoxicity, neurotransmission

DOI: 10.3233/JAD-2011-110503

Citation: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 447-455, 2011

Authors: Madsen, Karine | Neumann, Wolf-Julian | Holst, Klaus | Marner, Lisbeth | Haahr, Mette Thorlund | Lehel, Szabolcs | Knudsen, Gitte Moos | Hasselbalch, Steen Gregers

Article Type: Research Article

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 [11 C]SB207145 PET scan to measure the binding potential of the 5-HT4 receptor. All AD …patients and eight healthy controls additionally underwent a [11 C]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. Show more

Keywords: 5-HT4 receptor, Alzheimer's disease, amyloid, serotonin, PET

DOI: 10.3233/JAD-2011-110056

Citation: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 457-466, 2011

Authors: Quiroz-Baez, Ricardo | Ferrera, Patricia | Rosendo-Gutiérrez, Rigoberto | Morán, Julio | Bermúdez-Rattoni, Federico | Arias, Clorinda

Article Type: Research Article

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. Show more

Keywords: 3xTg-AD, amyloid-β protein, caspase-12, endoplasmic-reticulum, isolated nerve endings, synaptic apoptosis

DOI: 10.3233/JAD-2011-110326

Citation: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 467-476, 2011

Authors: Stein, Mark S. | Scherer, Samuel C. | Ladd, Kylie S. | Harrison, Leonard C.

Article Type: Research Article

Abstract: Poor vitamin D nutrition 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. Show more

Keywords: Alzheimer's disease, nasal insulin, randomized controlled trial, vitamin D

DOI: 10.3233/JAD-2011-110149

Citation: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 477-484, 2011

Authors: Hane, Francis | Drolle, Elizabeth | Gaikwad, Ravi | Faught, Erin | Leonenko, Zoya

Article Type: Research Article

Abstract: Amyloid fibril formation is generally associated with many neurodegenerative disorders, including Alzheimer's disease (AD). Although fibril plaque formation is associated with biological membranes in vivo, the role of the cell surfaces in amyloid fibril formation and the 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 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. Show more

Keywords: 1,2-dioleoyl-3-trimethylammonium-propane, DOTAP, 1,2-dioleoyl-sn-glycero-3-phosphocholine, DOPC, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, DPPC, 1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol), DOPG, Alzheimer's disease, amyloid-β1-42, amyloid fibril formation, amyloid-lipid interactions, atomic force microscopy

DOI: 10.3233/JAD-2011-102112

Citation: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 485-494, 2011

Authors: Wharton, Whitney | Baker, Laura D. | Gleason, Carey E. | Dowling, Maritza | Barnet, Jodi H. | Johnson, Sterling | Carlsson, Cynthia | Craft, Suzanne | Asthana, Sanjay

Article Type: Research Article

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 43 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. Show more

Keywords: Alzheimer's disease, clinical trial, cognition, estradiol, estrogen, hormone therapy, medroxyprogesterone, memory

DOI: 10.3233/JAD-2011-110341

Citation: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 495-505, 2011

Authors: Dragicevic, Natasa | Smith, Adam | Lin, Xiaoyang | Yuan, Fang | Copes, Neil | Delic, Vedad | Tan, Jun | Cao, Chuanhai | Shytle, R. Douglas | Bradshaw, Patrick C.

Article Type: Research Article

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. Show more

Keywords: Adenosine triphosphate, Alzheimer's disease, EGCG, flavonoids, membrane potential, mitochondrial, polyphenols, reactive oxygen species, respiration

DOI: 10.3233/JAD-2011-101629

Citation: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 507-521, 2011