Journal of Alzheimer's Disease - Volume 27, issue 3

Authors: Sluchanko, Nikolai N. | Gusev, Nikolai B.

Article Type: Review Article

Abstract: Aggregation of tau proteins followed by formation of paired helical filaments and neurofibrillary tangles is considered as a hallmark of certain neurodegenerative disorders such as different tauopathies and Alzheimer's disease (AD). Tau aggregation is dependent on the presence of polyanions, cellular redox state, limited proteolysis, and different posttranslational modifications among which tau phosphorylation plays a particularly important role. Although it is still debatable whether tau aggregation is harmful or protective for the cell, detailed analysis of molecular mechanisms underlying this process seems to be of great importance for understanding AD pathogenesis. This review is focused on universal adapter proteins 14-3-3 …that seem to be significant partners to tau protein in neurons. 14-3-3 interacts with nonphosphorylated tau and promotes its interaction with and phosphorylation by a number of protein kinases. 14-3-3 induces aggregation of nonphosphorylated tau and does not affect aggregation of tau phosphorylated at specific sites. Due to its high concentration in neurons, 14-3-3 can compete with tubulin for interaction with tau. Binding to phosphorylated tau, 14-3-3 might inhibit its dephosphorylation by protein phosphatases and by this means indirectly affect interaction of tau with microtubules and tau aggregation. Finally, 14-3-3 might promote sequestration of dangerous small tau oligomers and stabilize tau aggregates. We propose that 14-3-3 should be considered an important participant of the complex process of tau aggregation and as a potential therapeutic target in treating AD. Show more

Keywords: 14-3-3 proteins, Alzheimer's disease, phosphatases, phosphoprotein, phosphorylation, tau proteins

DOI: 10.3233/JAD-2011-110692

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 467-476, 2011

Authors: Saab, Bechara J. | Luca, Ruxandra M. | Yuen, Wing B. | Saab, Adam M.P. | Roder, John C.

Article Type: Short Communication

Abstract: Alzheimer's disease (AD) is multi-factorial mental disorder characterized by a copious array of congruent features cumulating in disrupted memory and dysthymia. Though the mechanism remains elusive, the highly unspecific pharmaceutical, memantine, provides modest benefits for patients with moderate-to-severe AD. A greater understanding of how memantine affects cognitive function promises to facilitate the search for better therapeutics. We therefore examined cognitive flexibility of mice following 5 and 10 mg/kg memantine administration using a platform re-location water maze. Strikingly, subjects receiving memantine demonstrated memory impairment relative to controls when re-trained off drug, revealing a novel and unusual disruption of cognitive flexibility.

Keywords: Alzheimer's disease, cognitive disorder, cognitive flexibility, dopamine, excitotoxicity, GABA(A), hippocampus, learning and memory, memantine, mental flexibility, mice, mouse, muscarinic cholinergic system, neurotoxicity, NMDAR, platform re-location water maze, prefrontal cortex

DOI: 10.3233/JAD-2011-110650

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 477-482, 2011

Authors: Mosconi, Lisa | de Leon, Mony | Murray, John | E, Lezi | Lu, Jianghua | Javier, Elizabeth | McHugh, Pauline | Swerdlow, Russell H.

Article Type: Research Article

Abstract: Biomarker studies demonstrate inheritance of glucose hypometabolism and increased amyloid-β deposition in adult offspring of mothers, but not fathers, affected by late-onset Alzheimer's disease (LOAD). The underlying genetic mechanisms are unknown. We investigated whether cognitively normal (NL) individuals with a maternal history of LOAD (MH) have reduced platelet mitochondrial cytochrome oxidase activity (COX, electron transport chain complex IV) compared to those with paternal (PH) or negative family history (NH). Thirty-six consecutive NL individuals (age 55 ± 15 y, range 27–71 y, 56% female, CDR = 0, MMSE ≥28, 28% APOE-4 carriers), including 12 NH, 12 PH, and 12 MH, received …a blood draw to measure platelet mitochondrial COX activity. Citrate synthase activity (CS) was measured as a reference. Groups were comparable for clinical and neuropsychological measures. We found that after correcting for CS, COX activity was reduced by 29% in MH compared to NH, and by 30% in MH compared to PH (p ≤ 0.006). Results remained significant controlling for age, gender, education, and APOE. No differences were found between PH and NH. COX measures discriminated MH from the other groups with accuracy ≥75%, and relative risk ≥3 (p ≤ 0.005). Among NL with LOAD-parents, only those with MH showed reduced COX activity in platelet mitochondria compared to PH and NH. The association between maternal history of LOAD and systemic COX reductions suggests transmission via mitochondrial DNA, which is exclusively maternally inherited in humans. Show more

Keywords: Early diagnosis, electron transport complex IV, late onset Alzheimer's disease, mitochondria

DOI: 10.3233/JAD-2011-110866

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 483-490, 2011

Authors: Verdelho, Ana | Madureira, Sofia | Moleiro, Carla | Santos, Catarina O. | Ferro, José M. | Erkinjuntti, Timo | Poggesi, Anna | Pantoni, Leonardo | Fazekas, Franz | Scheltens, Philip | Waldemar, Gunhild | Wallin, Anders | Inzitari, Domenico | and on behalf of the LADIS Study

Article Type: Research Article

Abstract: Memory complaints are frequent in the elderly but its implications in cognition over time remain a controversial issue. Our objective was to evaluate the risk of self perceived memory complaints in the evolution for future dementia. The LADIS (Leukoaraiosis and Disability) prospective multinational European study evaluates the impact of white matter changes (WMC) on the transition of independent elderly subjects into disability. Independent elderly were enrolled due to the presence of WMC. Subjects were evaluated yearly during 3 years with a comprehensive clinical protocol and a neuropsychological battery. Dementia and subtypes of dementia were classified. Self perceived memory complaints in …independent elderly were collected during the interview. MRI was performed at entry and at the end of the study. 639 subjects were included (74.1 ± 5 years old, 55% women, 9.6 ± 3.8 years of schooling). At end of follow-up, 90 patients were demented (vascular dementia, 54; Alzheimer's disease (AD) and AD with vascular component, 34; frontotemporal dementia, 2). Using Cox regression analysis, we found that self perceived memory complaints were a strong predictor of AD and AD with vascular component during the follow-up (β = 2.7, p = 0.008; HR = 15.5, CI 95% [2.04, 117.6]), independently of other confounders, namely depressive symptoms, WMC severity, medial temporal lobe atrophy, and global cognition status at baseline. Self perceived memory complaints did not predict vascular dementia. In the LADIS study, self perceived memory complaints predicted AD but not vascular dementia in elderly subjects with WMC living independently. Show more

Keywords: Aging, Alzheimer's disease, dementia, memory complaints, white matter changes

DOI: 10.3233/JAD-2011-110494

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 491-498, 2011

Authors: Puoliväli, Jukka | Nurmi, Antti | Miettinen, Taina-Kaisa | Soleti, Antonio | Riccardino, Francesca | Kalesnykas, Giedrius | Heikkinen, Taneli | Vartiainen, Nina | Pussinen, Raimo | Tähtivaara, Leena | Lehtimäki, Kimmo | Yrjänheikki, Juha | Canistro, Donatella | Sapone, Andrea | Spisni, Enzo | Paolini, Moreno

Article Type: Research Article

Abstract: The purpose of this study was to evaluate the efficacy of the radical scavenger IAC (bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl) decantionate) in alleviating behavioral deficits and reducing amyloid-β (Aβ) accumulation in an Alzheimer's disease (AD) transgenic Tg2576 mouse model. Daily treatment with IAC (3–30 mg/kg, i.p.) was started at the age of 6 months and continued until the mice were 13 months old. At the age of 9 months and again at 12 months, the mice were tested in open field and water maze tests. At the age of 13 months, the mice were sacrificed and the brains processed for immunohistochemistry. Mortality was significantly …reduced in all IAC-treated groups. In addition, IAC treatment improved the water maze hidden platform training performance but had no effect on motor activity in the open field or water maze swim speed in transgenic mice. Lastly, IAC treatment (10 mg/kg) significantly reduced the cortical Aβ plaque burden. In vitro, IAC is able to increase the number of neurites and neurite branches in cultured cortical primary neurons. In conclusion, IAC slowed down the development of the AD-like phenotype in Tg2576 mice and accelerated neurite growth in cultured neurons. Show more

Keywords: Alzheimer's disease, antioxidant, IAC (bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl) decantionate), Tg2576 mice

DOI: 10.3233/JAD-2011-110881

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 499-510, 2011

Authors: Bauer, Charlotte | Pardossi-Piquard, Raphaëlle | Dunys, Julie | Roy, Maggie | Checler, Frédéric

Article Type: Research Article

Abstract: Proteolytic degradation has emerged as a key pathway involved in controlling levels of the Alzheimer's disease (AD)-associated amyloid-β peptides (Aβ) in the brain. The ectopeptidase, neprilysin (NEP), has been reported as the major Aβ-degrading enzyme in mice and human brains. We have previously shown that NEP expression and activity are regulated by AICD, the intracellular domain of the amyloid-β protein precursor (AβPP) generated by γ-secretase. Thus, NEP transcription, expression, and enzymatic activity are dramatically reduced in fibroblasts devoid of AβPP (the precursor of AICD) or lacking both presenilin (PS) 1 and 2 (two parent proteins contributing to AICD formation). We …demonstrate here that NEP expression and activity are influenced by a number of cell passages and density, and we confirm a drastic reduction of NEP expression and activity in AβPP and PS null fibroblasts examined at similar passages and cell densities. Furthermore, Imatinib (Gleevec), a known tyrosine kinase inhibitor was recently shown to elevate AICD in H4 human neuroglioma cells, and this was accompanied by concomitant increases of NEP protein, mRNA levels, and activity. However, the demonstration of a causal link between Imatinib and AICD levels was still lacking. We show here an Imatinib-dependent effect on NEP expression and activity in murine fibroblasts and establish that Imatinib-induced modulation of NEP was abolished by the depletion of AβPP or its homologues APLP1 and APLP2, thereby confirming that Imatinib-mediated control of NEP could indeed be accounted for its effect on AICD. Show more

Keywords: AβPP-null fibroblasts, AICD, cell aging, cell density, HEK293 cells, imatinib, neprilysin, PS null fibroblasts, secretase

DOI: 10.3233/JAD-2011-110746

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 511-520, 2011

Authors: Kavanagh, Shane | Van Baelen, Bart | Schäuble, Barbara

Article Type: Research Article

Abstract: In Alzheimer's disease (AD), it is important to consider long-term effects, not only in patients receiving treatment, but also in subjects in whom therapy has been discontinued. The present analysis evaluates the long-term effects of galantamine on cognitive function in AD in terms of Mini-Mental State Examination (MMSE) scores for up to 7 years, using both clinical data and epidemiological modeling. Consideration is given not only to patients continuing to receive galantamine therapy, but also to those who stop this treatment. In a retrospective review of medical notes, re-contacted study investigators obtained data from 258 patients originally recruited into three …previously described randomized clinical trials involving galantamine: two placebo-controlled trials in mild-to-moderate AD (of 3 and 6 months' duration, followed by open-label extensions) and the galantamine-treatment arm of a 12-month comparative study with donepezil in moderate AD. Information relating to disease progression was collated (up to five MMSE scores, separated by at least 3 months, for each patient). Changes in MMSE scores over time were evaluated using observed data. In the absence of long-term placebo, the rate of cognitive decline without treatment was projected using a previously described epidemiological model. A new, exploratory statistical model was also developed. Results showed that patients with mild-to-moderate AD who received long-term galantamine treatment exhibited attenuated decline in cognitive function, as assessed by MMSE, compared with decline predicted in the absence of treatment. Furthermore, patients who stopped treatment experienced subsequent cognitive decline at a rate similar to that predicted for untreated patients. Show more

Keywords: Alzheimer's disease, biological model, cognitive symptoms, galantamine

DOI: 10.3233/JAD-2011-110417

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 521-530, 2011

Authors: Hashioka, Sadayuki | McLarnon, James G. | Ryu, Jae K. | Youssef, Amal M. | Abd-El-Aziz, Alaa S. | Neeland, Edward G. | Klegeris, Andis

Article Type: Research Article

Abstract: Pyrazole derivatives are well documented to possess anti-inflammatory activity but their effects on microglial activation are unknown. We determined the efficacy of the novel pyrazole compound 2-MBAPA (R/S-(±)-2-Methylbenzylamino 2-oxo-N-[4-cyano-1-phenyl-1H-pyrazol-5-yl] acetamide) on activated microglia under conditions relevant to inflammation in Alzheimer's disease (AD) brain. The compound at a non-toxic concentration inhibited secretion of tumor necrosis factor (TNF)-α by activated human microglia and attenuated toxicity of conditioned medium from activated human microglia towards human SH-SY5Y neuroblastoma cells in vitro. The 2-MBAPA neuroprotection was further demonstrated in vivo using an animal model of AD. The compound inhibited microgliosis, but not astrogliosis, in amyloid-β …peptide (Aβ)1-42 -injected rat brain. 2-MBAPA also diminished neuronal loss in the dentate gyrus caused by Aβ1-42 injection. These results indicate that this novel pyrazole compound confers neuroprotection by inhibiting microglial activation. Therefore, further studies with 2-MBAPA and novel analogues based on this lead compound are warranted in an effort to develop new pharmacological agents that may be useful for slowing down progression of AD and other neuroinflammatory disorders associated with activated microglia. Show more

Keywords: Amyloid-β peptide (Aβ1-42), animal model of Alzheimer's disease, microglia, neuroinflammation, neurotoxicity, pyrazole derivatives

DOI: 10.3233/JAD-2011-110698

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 531-541, 2011

Authors: Britt III, William G. | Hansen, Anne M. | Bhaskerrao, Sofia | Larsen, James P. | Petersen, Floyd | Dickson, April | Dickson, Cindy | Kirsch, Wolff M.

Article Type: Research Article

Abstract: The majority of mild cognitive impairment (MCI) studies use baseline and one follow-up measurement to determine the clinical course of the disorder. This report of MCI clinical course is based on the a statistical evaluation of multiple neurocognitive tests over a 60 month period in elderly normal and MCI cohorts. The data includes serial informant-based measures (Clinical Dementia Rating [CDR]) and a comprehensive battery of neuropsychological tests analyzed by two different regression methods. Twenty-nine elderly participants entered the study as neurocognitively normal; 26 remained normal, 2 progressed to MCI, and 1 progressed to dementia. Eighty-three participants entered the study as …multiple domain MCI cases; 10 became normal, 46 remained MCI, and 27 progressed to dementia. Three of the 27 demented died with full necropsies performed (one case was progressive supranuclear palsy and two confirmed Alzheimer's disease with severe cerebral amyloid angiopathy (CAA)). Without serial measures, 1 in 8 MCI could be misclassified as “stable MCI” despite reverting to normal. The stable MCI cohorts did not benefit from practice effects though the normal subjects did. Applying Classification and Regression Tree (CART) analysis enabled prediction of the endpoint status of participants from baseline values with 78.6% accuracy. The fluctuating cognitive status of the multiple domain MCI cases implies a remitting pathologic process with elements of recovery consistent with a progressive microvasculopathy such as CAA. Show more

Keywords: Informant-based evaluation, mild cognitive impairment, misdiagnosis, neuropsychological testing, practice effects, serial neurocognitive evaluations

DOI: 10.3233/JAD-2011-110740

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 543-551, 2011

Authors: Arab, Lenore | Biggs, Mary L. | O'Meara, Ellen S. | Longstreth, W.T. | Crane, Paul K. | Fitzpatrick, Annette L.

Article Type: Research Article

Abstract: Although caffeine can enhance cognitive function acutely, long-term effects of consumption of caffeine-containing beverages such as tea and coffee are uncertain. Data on 4,809 participants aged 65 and older from the Cardiovascular Health Study (CHS) were used to examine the relationship of consumption of tea and coffee, assessed by food frequency questionnaire, on change in cognitive function by gender. Cognitive performance was assessed using serial Modified Mini-Mental State (3MS) examinations, which were administered annually up to 9 times. Linear mixed models were used to estimate rates of change in standard 3MS scores and scores modeled using item response theory (IRT). …Models were adjusted for age, education, smoking status, clinic site, diabetes, hypertension, stroke, coronary heart disease, depression score, and APOE genotype. Over the median 7.9 years of follow-up, participants who did not consume tea or coffee declined annually an average of 1.30 points (women) and 1.11 points (men) on standard 3MS scores. In fully adjusted models using either standard or IRT 3MS scores, we found modestly reduced rates of cognitive decline for some, but not all, levels of coffee and tea consumption for women, with no consistent effect for men. Caffeine consumption was also associated with attenuation in cognitive decline in women. Dose-response relationships were not linear. These longitudinal analyses suggest a somewhat attenuated rate of cognitive decline among tea and coffee consumers compared to non-consumers in women but not in men. Whether this association is causal or due to unmeasured confounding requires further study. Show more

Keywords: Caffeine, coffee, cognition, tea

DOI: 10.3233/JAD-2011-110431

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 553-566, 2011