Journal of Alzheimer's Disease - Volume 39, issue 2

Authors: Métais, Charles | Brennan, Kathryn | Mably, Alex J. | Scott, Michael | Walsh, Dominic M. | Herron, Caroline E.

Article Type: Research Article

Abstract: Epidemiological evidence suggests that chronic treatment with simvastatin may protect against the development of Alzheimer's disease (AD), but as yet it is unclear how this effect is mediated. Extensive data also indicates that the amyloid β-protein (Aβ) plays a central role in the disease process, and it has been suggested that the protective effects of simvastatin may be mediated by reducing Aβ production or by counteracting the toxic effects of Aβ. Accordingly, using the AβPPswe/PS1dE9 mouse model of AD, we investigated the effects of simvastatin on long-term potentiation (LTP), amyloid biology, and two key kinases involved in Aβ-mediated toxicity. Since …burgeoning data indicate that both fibrillar and non-fibrillar forms of Aβ play a prominent role in AD pathogenesis, we were careful to investigate the effects of simvastatin on three biochemically distinct pools of Aβ. In untreated AβPPswe/PS1dE9 mice, there was a dramatic and significant increase in the levels of water-soluble Aβ between 6 and 8 months, but this remained constant between 8 and 18 months. In contrast, the concentrations of detergent-soluble and formic acid (FA)-soluble Aβ species increased across all ages examined, thus demonstrating that while amyloid deposition continued, the levels of water-soluble Aβ remained relatively constant. LTP was normal at 6 months, but was significantly impaired at 8 and 18 months. Importantly, a diet supplemented with 0.04% simvastatin for one month (at 7 months) positively affected synaptic plasticity in AβPPswe/PS1dE9 mice and did not significantly alter levels of water-soluble, detergent-soluble, or FA-soluble Aβ, but did increase phosphorylation of both Akt and GSK-3, while tau and tau phosphorylation were unaltered. These results indicate that the protective effects of simvastatin may be mediated by maintaining signaling pathways that help to protect and rescue LTP. Show more

Keywords: Alzheimer's disease, amyloid-β, hippocampus, long-term potentiation, statin

DOI: 10.3233/JAD-130257

Citation: Journal of Alzheimer's Disease, vol. 39, no. 2, pp. 315-329, 2014

Authors: Xian, Yan-Fang | Mao, Qing-Qiu | Wu, Justin CY | Su, Zi-Ren | Chen, Jian-Nan | Lai, Xiao-Ping | Ip, Siu-Po | Lin, Zhi-Xiu

Article Type: Research Article

Abstract: The progressive accumulation of amyloid-β (Aβ) in the form of senile plaques has been recognized as a key causative factor leading to the cognitive deficits seen in Alzheimer's disease (AD). Recent evidence indicates that Aβ induces neurotoxicity in the primary neuronal cultures as well as in the brain. Previously, we have demonstrated that isorhynchophylline (IRN), the major chemical ingredient of Uncaria rhynchophylla, possessed potent neuroprotective effects. In the present study, we aimed to investigate the effect of IRN on cognitive function, neuronal apoptosis, and tau protein hyperphosphorylation in the hippocampus of the Aβ25-35 -treated rats and to elucidate its action …mechanisms. We showed that Aβ25-35 injection caused spatial memory impairment, neuronal apoptosis, and tau protein hyperphosphorylation. Treatment with IRN (20 or 40 mg/kg) for 21 days could significantly ameliorate the cognitive deficits induced by Aβ25-35 in the rats. In addition, IRN attenuated the Aβ25-35 -induced neuronal apoptosis in hippocampus by down-regulating the protein and mRNA levels of the ratio of Bcl-2/Bax, cleaved caspase-3 and caspase-9, as well as suppressing the tau protein hyperphosphorylation at the Ser396, Ser404, and Thr205 sites. Mechanistic study showed that IRN could inhibit the glycogen synthase kinase 3β (GSK-3β) activity, and activate the phosphorylation of phosphatidylinositol 3-kinase (PI3K) substrate Akt. These results indicate that down-regulation of GSK-3β activity and activation of PI3K/Akt signaling pathway are intimately involved in the neuroprotection of IRN. The experimental findings provide further evidence to affirm the potential of IRN as a worthy candidate for further development into a therapeutic agent for AD and other tau pathology-related neurodegenerative diseases. Show more

Keywords: Amyloid-β, apoptosis, isorhynchophylline, PI3K/Akt signaling pathway, spatial memory, tau protein hyperphosphorylation

DOI: 10.3233/JAD-131457

Citation: Journal of Alzheimer's Disease, vol. 39, no. 2, pp. 331-346, 2014

Authors: Francis, Beverly M. | Yang, Jimao | Song, Byung Jun | Gupta, Saurabh | Maj, Mary | Bazinet, Richard P. | Robinson, Brian | Mount, Howard T.J.

Article Type: Research Article

Abstract: Bioenergetic failure is a feature of Alzheimer's disease (AD). We examined mitochondrial function in the amyloid-β protein precursor transgenic ‘TgCRND8’ mouse model of AD. Activities of NADH: cytochrome c reductase (complex I + III) and cytochrome oxidase (complex IV) of the electron transport chain, as well as those of α-ketoglutarate dehydrogenase (α-KGDH) and pyruvate dehydrogenase (PDH) were assessed in brains of 45 week-old mice. Complex I + III activity was reduced by almost 50%, whereas complex IV, α-KGDH, and PDH activities were unaffected. Reduced activity coincided with decreased expression of NDUFB8, a nuclear-DNA encoded subunit integral to the assembly of …complex I. The composition and availability of cardiolipin, a major phospholipid in inner mitochondrial membranes, was not altered. To determine whether mitochondrial output is affected by the selective reduction in complex I + III activity, we examined tissue levels of high-energy phosphates. ATP was maintained whereas creatine increased in the cortex and hippocampus. These results suggest disruption of complex I function and the likely role of creatine in sustaining ATP at late stages of dysfunction in TgCRND8 mice. Show more

Keywords: Alzheimer's disease, amyloid, ATP, cardiolipin, creatine, electron transport chain, NDUFB8

DOI: 10.3233/JAD-131499

Citation: Journal of Alzheimer's Disease, vol. 39, no. 2, pp. 347-355, 2014

Authors: Ribeiro, Carlos A. | Oliveira, Sandra Marisa | Guido, Luis F. | Magalhães, Ana | Valencia, Gregorio | Arsequell, Gemma | Saraiva, Maria João | Cardoso, Isabel

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most common form of dementia and now represents 50–70% of total dementia cases. Over the last two decades, transthyretin (TTR) has been associated with AD and, very recently, a novel concept of TTR stability has been established in vitro as a key factor in TTR/amyloid-β (Aβ) interaction. Small compounds, TTR stabilizers (usually non-steroid anti-inflammatory drugs), bind to the thyroxine (T4 ) central binding channel, increasing TTR tetrameric stability and TTR/Aβ interaction. In this work, we evaluated in vivo the effects of one of the TTR stabilizers identified as improving TTR/Aβ interaction, iododiflunisal (IDIF), in Aβ …deposition and other AD features, using AβPPswe/PS1A246E transgenic mice, either carrying two or just one copy of the TTR gene (AD/TTR+/+ or AD/TTR+/− , respectively), available and characterized in our laboratory. The results showed that IDIF administered orally bound TTR in plasma and stabilized the protein, as assessed by T4 displacement assays, and was able to enter the brain as revealed by mass spectrometry analysis of cerebrospinal fluid. TTR levels, both in plasma and cerebrospinal fluid, were not altered. In AD/TTR+/− mice, IDIF administration resulted not only in decreased brain Aβ levels and deposition but also in improved cognitive function associated with the AD-like neuropathology in this mouse model, although no improvements were detectable in the AD/TTR+/+ animals. Further, in AD/TTR+/− mice, Aβ levels were reduced in plasma suggesting TTR promoted Aβ clearance from the brain and from the periphery. Taken together, these results strengthen the importance of TTR stability in the design of therapeutic drugs, highlighting the capacity of IDIF to be used in AD treatment to prevent and to slow the progression of the disease. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, behavior, cerebrospinal fluid, iododiflunisal, plasma, transgenic mouse, transthyretin

DOI: 10.3233/JAD-131355

Citation: Journal of Alzheimer's Disease, vol. 39, no. 2, pp. 357-370, 2014

Authors: Lo, Ada H.Y. | Woodman, Richard J. | Pachana, Nancy A. | Byrne, Gerard J. | Sachdev, Perminder S.

Article Type: Research Article

Abstract: Background: Smoking, excessive drinking, and physical inactivity are associated with reduced cognitive function but the independence, domain specific cognitive effects, and trajectories of these associations are not firmly established. Objective: Our aim was to examine these lifestyle-cognitive function associations in middle-to-older aged women across time. Methods: Cohort study design with repeat surveys (2001, 2005, and 2008). Participants were volunteers from a random sample of Australian women on the Brisbane electoral roll; mean (±SD) age 60 ± 11 years in 2001. Outcome measures were the Mini-Mental State Examination (MMSE), Auditory Delayed Index (ADI), Visual Delayed Index (VDI), …Working Memory Index (WMI), and Processing Speed Index (PSI). Results: 489 women completed cognitive testing in 2001, 451 in 2005, and 376 in 2008. Mean (±SD) cognitive scores in 2001 were MMSE: 29.1 ± 1.2, ADI: 104.6 ± 13.4, VDI: 107.2 ± 14.0, WMI: 104.1 ± 12.3, and PSI: 102.7 ± 11.8. Multivariate adjusted mean scores (95% CI) over the 7-year study period were higher for moderate drinkers than non-drinkers for the MMSE (β = 0.32; 0.04, 0.61), the VDI (β = 4.33; 0.96, 7.70), and the WMI (β = 3.21; 0.34, 6.07). Current smokers performed worse than never-smokers for the MMSE (β = −0.35; 0.64, −0.06), the VDI (β = −3.91; −7.57, −0.26), the WMI (β = −3.42; −6.67, −0.18), and the PSI (β = −5.89; −8.91, −2.87). PSI was higher in women performing strenuous physical activity compared to inactive women (β = 2.14; 0.37, 3.90). None of the three lifestyle parameters influenced the changes in cognition across time. Conclusions: Alcohol and exercise were associated with selective protective effects and tobacco with selective harmful effects on cognitive function in middle-to-older aged women. Associations remained consistent across time. Show more

Keywords: Cognitive function, drinking, physical activity smoking, women

DOI: 10.3233/JAD-130971

Citation: Journal of Alzheimer's Disease, vol. 39, no. 2, pp. 371-383, 2014

Authors: Morawski, Markus | Schilling, Stephan | Kreuzberger, Moritz | Waniek, Alexander | Jäger, Carsten | Koch, Birgit | Cynis, Holger | Kehlen, Astrid | Arendt, Thomas | Hartlage-Rübsamen, Maike | Demuth, Hans-Ulrich | Roßner, Steffen

Article Type: Research Article

Abstract: Brains of Alzheimer's disease (AD) patients are characterized in part by the formation of high molecular weight aggregates of amyloid-β (Aβ) peptides, which interfere with neuronal function and provoke neuronal cell death. The pyroglutamate (pGlu) modification of Aβ was demonstrated to be catalyzed by the enzyme glutaminyl cyclase (QC) and to enhance pathogenicity and neurotoxicity. Here, we addressed the role of QC in AD pathogenesis in human cortex. Two sets of human postmortem brain tissue from a total of 13 non-demented controls and 11 AD cases were analyzed by immunohistochemistry and unbiased stereology, quantitative RT-PCR, and enzymatic activity assays for …the expression level of QC in temporal and entorhinal cortex. Additionally, cortical Aβ and pGlu-Aβ concentrations were quantified by ELISA. Data on QC expression and Aβ peptide concentrations were correlated with each other and with the Mini-Mental State Examination (MMSE) of individual cases. In control cases, QC expression was higher in the more vulnerable entorhinal cortex than in temporal cortex. In AD brains, QC mRNA expression and the immunoreactivity of QC were increased in both cortical regions and frequently associated with pGlu-Aβ deposits. The analyses of individual cases revealed significant correlations between QC mRNA levels and the concentration of insoluble pGlu-Aβ aggregates, but not of unmodified Aβ peptides. Elevated pGlu-Aβ load showed a better correlation with the decline in MMSE than elevated concentration of unmodified Aβ. Our observations provide evidence for an involvement of QC in AD pathogenesis and cognitive decline by QC-catalyzed pGlu-Aβ formation. Show more

Keywords: Alzheimer's disease, entorhinal cortex, glutaminyl cyclase, pyroglutamate-Aβ, Mini-Mental State Examination

DOI: 10.3233/JAD-131535

Citation: Journal of Alzheimer's Disease, vol. 39, no. 2, pp. 385-400, 2014

Authors: Coelho, Flávia Gomes de Melo | Vital, Thays Martins | Stein, Angelica Miki | Arantes, Franciel José | Rueda, André Veloso | Camarini, Rosana | Teodorov, Elizabeth | Santos-Galduróz, Ruth Ferreira

Article Type: Research Article

Abstract: Studies indicate the involvement of brain-derived neurotrophic factor (BDNF) in the pathogenesis of Alzheimer's disease (AD). Decreased BDNF levels may constitute a lack of trophic support and contribute to cognitive impairment in AD. The benefits of acute and chronic physical exercise on BDNF levels are well-documented in humans, however, exercise effects on BDNF levels have not been analyzed in older adults with AD. The aim of this study was to investigate the effects of acute aerobic exercise on BDNF levels in older adults with AD and to verify associations among BDNF levels, aerobic fitness, and level of physical activity. Using …a controlled design, twenty-one patients with AD (76.3 ± 6.2 years) and eighteen healthy older adults (74.6 ± 4.7 years) completed an acute aerobic exercise. The outcomes included measures of BDNF plasma levels, aerobic fitness (treadmill grade, time to exhaustion, VO2, and maximal lactate) and level of physical activity (Baecke Questionnaire Modified for the Elderly). The independent t-test shows differences between groups with respect to the BDNF plasma levels at baseline (p = 0.04; t = 4.53; df = 37). In two-way ANOVA, a significant effect of time was found (p = 0.001; F = 13.63; df = 37), the aerobic exercise significantly increased BDNF plasma levels in AD patients and healthy controls. A significant correlation (p = 0.04; r = 0.33) was found between BDNF levels and the level of physical activity. The results of our study suggest that aerobic exercise increases BDNF plasma levels in patients with AD and healthy controls. In addition to that, BDNF levels had association with level of physical activity. Show more

Keywords: Aerobic exercise, Alzheimer's disease, brain-derived neurotrophic factor, neurotrophic factors, physical activity

DOI: 10.3233/JAD-131073

Citation: Journal of Alzheimer's Disease, vol. 39, no. 2, pp. 401-408, 2014

Authors: Jacobs, Heidi I.L. | Clerx, Lies | Gronenschild, Ed H.B.M. | Aalten, Pauline | Verhey, Frans R.J.

Article Type: Research Article

Abstract: White matter hyperintensities are associated with an increased risk of Alzheimer's disease (AD). White matter hyperintensities are believed to disconnect brain areas. We examined the topographical association between white matter hyperintensities and cortical thickness in controls, mild cognitive impairment (MCI), and AD patients. We examined associations between white matter hyperintensities and cortical thickness among 18 older cognitively healthy participants, 18 amnestic MCI, and 17 mild AD patients. These associations were cluster-size corrected for multiple comparisons. In controls, a positive association between white matter hyperintensities and cortical thickness was found in lateral temporal gyri. In MCI patients, white matter hyperintensities were …positively related to cortical thickness in frontal, temporal, and parietal areas. Positive associations between white matter hyperintensities and cortical thickness in AD patients were confined to parietal areas. The results of the interaction group by white matter hyperintensities on cortical thickness were consistent with the findings of positive associations in the parietal lobe for MCI and AD patients separately. In the frontal areas, controls and AD patients showed inverse associations between white matter hyperintensities and cortical thickness, while MCI patients still showed a positive association. These results suggest that a paradoxical relationship between white matter hyperintensities and cortical thickness could be a consequence of neuroinflammatory processes induced by AD-pathology and white matter hyperintensities. Alternatively, it might reflect a region-specific and disease-stage dependent compensatory hypertrophy in response to a compromised network. Show more

Keywords: Compensation, cortical thickness, dementia, hypertrophy, inflammation, white matter hyperintensities

DOI: 10.3233/JAD-131232

Citation: Journal of Alzheimer's Disease, vol. 39, no. 2, pp. 409-422, 2014

Authors: Darreh-Shori, Taher | Hosseini, Sharokh Makvand | Nordberg, Agneta

Article Type: Research Article

Abstract: Despite three decades of intensive research in the field of Alzheimer's disease (AD) and numerous clinical trials of new therapeutic agents, cholinesterase inhibitors (ChEIs) are still the mainstay of therapeutics for AD and dementia with Lewy bodies. Pharmacodynamic analyses of ChEIs provide paradoxical observations. Treatment with the rapidly reversible, noncarbamylating ChEIs (donepezil, galantamine, and tacrine) increases acetylcholinesterase (AChE) protein expression, whereas the carbamylating agent, rivastigmine, produces sustained inhibition with no significant change in AChE protein expression. Still, the symptomatic clinical efficacies of all these agents are similar. We report here for the first time that treatment with phenserine, another carbamylating …ChEI, produces a sustained but mild inhibition of AChE in cerebrospinal fluid (CSF) of AD patients. We also show that phenserine treatment reverses donepezil-induced elevation of AChE expression. Further analyses on CSF of another larger patient cohort treated with donepezil revealed that, in addition to its main mode of action, donepezil produced two other pharmacodynamics with potentially contradictory outcomes. Donepezil-induced AChE expression favored an AChE-driven amyloid-β peptide (Aβ) aggregation, whereas donepezil itself concentration-dependently counteracted the AChE-induced Aβ aggregation, most likely by competing with the Aβ peptides for peripheral anionic site on the AChE protein. The reduction of AChE protein expression in the donepezil-treated patients by concomitant administration of the carbamylating agent, phenserine, could allow the donepezil molecule to only prevent interaction between Aβ and AChE. The current study suggests that an add-on therapy with a low-dose formulation of a carbamylating agent in patients on long-term donepezil treatment should be explored as a strategy for enhancing the clinical efficacy of these agents in dementia disorders. Show more

Keywords: Add-on therapy, Alzheimer's disease, carbamylating ChEIs, cholinesterase inhibitors (ChEIs), donepezil, peripheral anionic site, phenserine, rivastigmine

DOI: 10.3233/JAD-130845

Citation: Journal of Alzheimer's Disease, vol. 39, no. 2, pp. 423-440, 2014

Authors: Perez-Garmendia, Roxanna | Hernandez-Zimbron, Luis Fernando | Morales, Miguel Angel | Luna-Muñoz, José | Mena, Raul | Nava-Catorce, Miriam | Acero, Gonzalo | Vasilevko, Vitaly | Viramontes-Pintos, Amparo | Cribbs, David H. | Gevorkian, Goar

Article Type: Research Article

Abstract: The main amyloid-β peptide (Aβ) variants detected in the human brain are Aβ1-40 and Aβ1-42 ; however, a significant proportion of Aβ in Alzheimer's disease (AD) brain also consists of N-terminal truncated/modified species. AβN3(pE), Aβ peptide bearing amino-terminal pyroglutamate at position 3, has been demonstrated to be a major N-truncated/modified constituent of intracellular, extracellular, and vascular Aβ deposits in AD and Down syndrome brain tissue. It has been previously demonstrated that rabbits fed a diet enriched in cholesterol and given water containing trace copper levels developed AD-like pathology including intraneuronal and extracellular Aβ accumulation, tau hyperphosphorylation, vascular inflammation, astrocytosis, …microgliosis, reduced levels of acetylcholine, as well as learning deficits and thus, may be used as a non-transgenic animal model of sporadic AD. In the present study, we have demonstrated for the first time the presence of AβN3(pE) in blood vessels in cholesterol-enriched diet-fed rabbit brain. In addition, we detected AβN3(pE) immunoreactivity in all postmortem AD brain samples studied. We believe that our results are potentially important for evaluation of novel therapeutic molecules/strategies targeting Aβ peptides in a suitable non-transgenic animal model. Show more

Keywords: Alzheimer's disease, amyloid-β, animal model, cholesterol-fed rabbit, pyroglutamate-modified amyloid

DOI: 10.3233/JAD-130590

Citation: Journal of Alzheimer's Disease, vol. 39, no. 2, pp. 441-455, 2014