Journal of Alzheimer's Disease - Volume 33, issue 1

Authors: Portelius, Erik | Olsson, Maria | Brinkmalm, Gunnar | Rüetschi, Ulla | Mattsson, Niklas | Andreasson, Ulf | Gobom, Johan | Brinkmalm, Ann | Hölttä, Mikko | Blennow, Kaj | Zetterberg, Henrik

Article Type: Research Article

Abstract: The Chinese hamster ovary cell line 7PA2, stably transfected with the 751 amino acid isoform of amyloid-β protein precursor (AβPP) containing the Val → Phe mutation at residue 717, is one of the most used models to study the biochemistry and toxicity of secreted amyloid-β (Aβ) peptides, particularly Aβ oligomers, which are considered to be of relevance to the pathogenesis of Alzheimer's disease. Here, we present a detailed immunochemical and mass spectrometric characterization of primary structures of Aβ peptides secreted by 7PA2 cells. Immunoprecipitation and western blot of 7PA2 cell culture media revealed abundant anti-Aβ immunoreactive bands in the molecular …weight range of 4–20 kDa. Mass spectrometric analysis showed that these bands contain several AβPP/Aβ peptides, starting at the N-terminal of the Aβ sequence and extending across the BACE1 cleavage site. Treatment of cells with a BACE1 inhibitor decreased the abundance of the Aβ monomer band by western blot and resulted in lower levels of Aβ1-40 , Aβ1-42 , and sAβPPβ as measured by ELISA. However, western blot bands thought to represent oligomers of Aβ increased in response to BACE1 inhibition. This increase was paralleled by the emergence of N-terminally truncated Aβ species (Aβ5-40 in particular) and Aβ species that spanned the β-secretase site in AβPP according to mass spectrometric analyses. The formation of these AβPP/Aβ peptides may have implications for the use of the 7PA2 cell line as a model for Aβ pathology. The enzyme(s) responsible for this particular BACE1-independent AβPP-processing remains to be identified. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarkers, dimers, mass spectrometry, oligomers

DOI: 10.3233/JAD-2012-120994

Citation: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 85-93, 2013

Authors: Ruzali, Wan Adriyani W. | Kehoe, Patrick G. | Love, Seth

Article Type: Research Article

Abstract: Vascular deposition of amyloid-β (Aβ) leads to the death of cerebrovascular smooth muscle cells (CVSMCs) in cerebral amyloid angiopathy (CAA). Apolipoprotein E (APOE) genotype influences the severity of CAA and development of vasculopathic complications. We have studied the relationship between uptake of Aβ into human CVSMCs and cell death, and the influence of ApoE isoforms on this process. We found that both Aβ42 and Aβ40 were taken up by human CVSMCs, and that this uptake—particularly that of Aβ42 —caused disruption to smooth muscle actin and cell death. Uptake of Aβ42 was partially blocked by the addition of …receptor-associated protein (RAP), implicating low-density lipoprotein receptor-related protein-1 (LRP-1) as the cell surface receptor. RAP significantly reduced the death of CVSMCs exposed to Aβ42 . In further experiments, CVSMCs were exposed to Aβ42 in the presence of the different isoforms of exogenous ApoE and high-density lipoprotein (HDL). All three isoforms of ApoE in the presence of HDL (HDL-ApoE) reduced the uptake of fluorescein-tagged Aβ42 but only HDL-ApoE3 significantly decreased cell death. We conclude that HDL-ApoE3, acting as an Aβ chaperone molecule, significantly reduces the death of CVSMCs that result from LRP-1-mediated uptake of Aβ. This may contribute to the differential effects of APOE genotype on severity of CAA and the risk of rupture of Aβ-laden blood vessels. Show more

Keywords: Amyloid-β, apolipoprotein E, cell death, cerebral amyloid angiopathy, low-density lipoprotein receptor-related protein-1, receptor associated protein, smooth muscle cell

DOI: 10.3233/JAD-2012-121336

Citation: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 95-110, 2013

Authors: Sabbagh, Marwan | Malek-Ahmadi, Michael | Levenson, Ian | Sparks, D. Larry

Article Type: Research Article

Abstract: KIF6 719Arg allele carriers are thought to have a greater lipid lowering response from statin therapy than non-carriers. Given the continued interest in the relationship between cholesterol, statin use, amnestic mild cognitive impairment (aMCI), and Alzheimer's disease (AD), investigating the role of KIF6 719Arg carrier status in these relationships may be of importance. Data from 86 patients (36 aMCI, 50 AD) with an average age of 76.87 ± 8.22 years were used for this study. Total cholesterol (TC), low density lipoprotein (LDL), high density lipoprotein (HDL), and triglycerides were the outcome variables. 719Arg carriers taking statins had significantly lower TC …(p < 0.001) and LDL (p < 0.001) levels than 719Arg carriers not taking statins. In addition, 719Arg carriers not taking statins had significantly higher TC (p = 0.004) and LDL (p < 0.001) than 719Arg non-carriers taking statins. Additional analyses indicated that ApoE ε4 carrier status and statin use interaction is also associated with lower TC (p = 0.04), but not LDL (p = 0.06). The interaction between 719Arg and ApoE ε4 carrier status on TC and LDL was not significant. This study is the first to demonstrate an association between lower cholesterol levels and statin use among KIF6 719Arg allele carriers with aMCI and AD. Accounting for 719Arg carrier status may be important in future studies investigating the link between cholesterol and AD and also for AD and aMCI clinical trials using statins as a treatment. Show more

Keywords: Alzheimer's disease, apolipoprotein E4, cholesterol, KIF6, mild cognitive impairment

DOI: 10.3233/JAD-2012-121015

Citation: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 111-116, 2013

Authors: Le Bastard, Nathalie | Coart, Els | Vanderstichele, Hugo | Vanmechelen, Eugeen | Martin, Jean-Jacques | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: Combined analysis of the Alzheimer's disease (AD) biomarkers amyloid-β1-42 (Aβ1-42 ), total tau (T-tau), and hyperphosphorylated tau (P-tau181P ) in cerebrospinal fluid (CSF) reduces the uncertainty associated with clinical dementia diagnosis. The present study evaluated the diagnostic accuracy of the CSF biomarker concentrations obtained with a multi-analyte Luminex assay (INNO-BIA AlzBio3) in comparison to single-analyte ELISA tests (INNOTEST). Data from 66 pathologically-confirmed dementia patients (51 AD and 15 non-AD) and 95 controls were included. Cut-off values were determined for each individual biomarker determined using both methods for different diagnostic challenges (dementia-controls; AD-controls; AD-non-AD). Comparing the diagnostic accuracy of individual …cut-off values between INNO-BIA and INNOTEST, no relevant differences could be identified. Logistic regression was used in addition to identify the best combination of predictor variables (biomarkers). Discrimination of dementia patients from controls using Aβ1-42 and T-tau yielded a diagnostic accuracy of 0.87 and 0.90 for INNO-BIA and INNOTEST, respectively. Discriminating AD patients from controls, the diagnostic accuracy was 0.90 and 0.93 for INNO-BIA and INNOTEST, respectively. Optimal discrimination of AD and non-AD patients was achieved by combining Aβ1-42 and P-tau181P (diagnostic accuracy = 0.86). In conclusion, which AD biomarkers or combination thereof are most informative is dependent on the differential diagnosis, but the clinical value of these markers in each of the differential diagnoses is independent of the method by which concentrations are determined. Since the clinical value of the ELISA (INNOTEST) and Luminex (INNO-BIA) tests is comparable, further research to select the most suitable analytical platform for routine CSF biomarker measurements is needed. Show more

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, immunoassay

DOI: 10.3233/JAD-2012-121246

Citation: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 117-131, 2013

Authors: Pinton, Simone | Sampaio, Tuane Bazanella | Ramalho, Rita M. | Rodrigues, Cecília M.P. | Nogueira, Cristina Wayne

Article Type: Research Article

Abstract: The purpose of this study was to investigate possible molecular targets involved in the neuroprotective effect of p,p′-methoxyl-diphenyl diselenide [(MeOPhSe)2 ], using a streptozotocin (STZ)-induced sporadic dementia of Alzheimer's type rat model. Male Wistar rats were injected with STZ (1.0 mg/8 μl; 4 μl/ventricle). After 21 days of STZ injection, regular diet-fed rats were supplemented with 10 ppm of (MeOPhSe)2 during 30 days. At the end of this period, rats performed object recognition and step-down passive avoidance tasks. Apoptosis was assessed by TUNEL staining and active caspase-3. Glial fibrillary acidic protein, ionized calcium binding adaptor molecule 1, and microtubule …associated protein 2 were determined by immunofluorescence in rat hippocampus. The results demonstrate that the (MeOPhSe)2 dietary supplementation reversed STZ-induced memory impairment by enhancing memory in sham rats. (MeOPhSe)2 was also effective in reducing STZ-induced apoptosis and preserving dendrites and synapses. Moreover, (MeOPhSe)2 inhibited activation of microglia and astrogliosis induced by STZ in the rat hippocampus. We conclude that the (MeOPhSe)2 neuroprotective action is related to inhibition of apoptosis and suppression of inflammation. Show more

Keywords: Apoptosis, glial cells, memory, neuroinflammation, organoselenium compounds, streptozotocin

DOI: 10.3233/JAD-2012-121150

Citation: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 133-144, 2013

Authors: Karlsson, Tobias E. | Karlén, Alexandra | Olson, Lars | Josephson, Anna

Article Type: Research Article

Abstract: In the search for molecules that may alter the formation of amyloid-β (Aβ) protofibrils, it has been shown that the Nogo-system can interact and bind to amyloid-β protein precursor and thus affect the amount of Aβ that is formed and deposited in the brain. To further address this issue in vivo, we crossed mice that overexpress Nogo receptor 1 (NgR1), “MemoFlex”, in forebrain neurons, with plaque forming APPswe/PSEN1(ΔE9) mice, to investigate if increased levels of NgR1 would influence plaque load or cognitive function in the resulting MemoFlex/APPswe/PSEN1(ΔE9) transgenic mice. We used a radial arm water maze and the Morris water …maze to measure cognitive function. We did not find any significant effect of NgR1 overexpression on the performance of APPswe/PSEN1(ΔE9) mice in the radial arm water maze test. However, MemoFlex/APPswe/PSEN1(ΔE9) mice were found to be significantly impaired in the Morris water maze. We also analyzed the amount of plaques in the two mouse models without finding any significant difference in plaque load in the cerebral cortex or the hippocampal formation. It therefore appears that overexpression of NgR1 in APPswe/PSEN1(ΔE9) mice does not have any marked effects on Aβ levels, yet appears to impair spatial cognitive abilities. We conclude that strong overexpression of NgR1 in forebrain neurons impairs aspects of cognitive function but does not markedly alter plaque load in plaque-forming APPswe/PSEN1(ΔE9) mice. Thus high levels of membrane-bound NgR1 present since early postnatal life does not influence the development of plaques in mice carrying the two human plaque-causing mutations APPswe and PSEN1(ΔE9). Show more

Keywords: Amyloid, amyloid beta-protein (40-42), maze learning, NOGO-receptor, RTN4r, plaque

DOI: 10.3233/JAD-2012-120493

Citation: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 145-155, 2013

Authors: Lönnroos, Eija | Kyyrönen, Pentti | Bell, J. Simon | van der Cammen, Tischa J.M. | Hartikainen, Sirpa

Article Type: Research Article

Abstract: Few studies have reported the risk of death related to Alzheimer's disease (AD) in large population-based cohorts. The objective of this study was to analyze the impact of AD on all-cause mortality in a nationwide sample of persons with AD. Community-dwelling persons with AD and an equal number of individually matched (age, gender, and region of residence) control persons without AD were identified from the registers of Social Insurance Institution of Finland at the end of 2005. Deaths in this sample (n = 56,041, mean age 79.7 years, 67.8% women) during a 57-month follow-up period were recorded. Using a nested …case-control design, unadjusted and adjusted (cardiovascular disease, cancer, diabetes, and asthma and/or COPD) hazard ratios (HR) with 95% confidence intervals (CI) were computed using proportional hazards regression. The results were categorized according to age at death (<80, 80 to 89, ≥90 years) and duration of AD (≤3, 4 to 6, ≥7 years). The unadjusted HR for death associated with AD was 2.03 (95% CI: 1.97 to 2.09). The HR was highest in the youngest age category [HR = 3.46 (95% CI: 3.18 to 3.77)], and still significantly elevated in the oldest age category [HR = 1.50 (95% CI: 1.41 to 1.60)]. Comorbidity adjustments did not change the HRs, and even a short duration of AD (≤3 years) was associated with a significantly increased risk of death. In conclusion, AD was associated with an increased risk of death that was more pronounced at younger ages and existed even after a recent diagnosis of AD. Show more

Keywords: Alzheimer's disease, case-control study, mortality, register-based

DOI: 10.3233/JAD-2012-120808

Citation: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 157-164, 2013

Authors: Chirila, Florin V. | Khan, Tapan K. | Alkon, Daniel L.

Article Type: Research Article

Abstract: Drugs to treat Alzheimer's disease (AD) have been unsuccessful in preventing its devastating cognitive deficits and progressive neurodegeneration. The lack of a definitive diagnostic for AD has been a major obstacle to AD drug discovery. Here, we describe a novel, highly accurate peripheral diagnostic for AD patients based on quantitatively measured complexity of skin-sampled fibroblast networks. A significant number of samples were studied under double-blind conditions and had autopsy and/or genetic validation. An additional sample confirmed the diagnostic discrimination on freshly obtained skin samples. A sub-sample of these diagnostic differences were induced by oligomerized amyloid-β1-42 . Based on the accuracy …of these measures that utilize physical principles such as fractal dimension and lacunarity as well as the significant correlation with disease duration, this biomarker profile appears to identify accurately AD patients for therapeutic intervention. Show more

Keywords: Alzheimer disease, biomarkers, cell aggregation, cell migration, diagnosis, fractal dimension, lacunarity, networks

DOI: 10.3233/JAD-2012-120745

Citation: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 165-176, 2013

Authors: Broersen, Laus M. | Kuipers, Almar A.M. | Balvers, Martin | van Wijk, Nick | Savelkoul, Paul J.M. | de Wilde, Martijn C. | van der Beek, Eline M. | Sijben, John W.C. | Hageman, Robert J.J. | Kamphuis, Patrick J.G.H. | Kiliaan, Amanda J.

Article Type: Research Article

Abstract: Diet is an important lifestyle factor implicated in the etiology of Alzheimer's disease (AD), but so far it is not fully elucidated to which nutrients the suggested protective effect of diet can be attributed. Recent evidence obtained in the amyloid-β 1-42 (Aβ42 ) infusion model in rats has shown that a multi-nutrient intervention known as Fortasyn™ Connect (FC) may protect the central cholinergic system against Aβ42 -induced toxicity. FC comprises the nutritional precursors and cofactors for membrane synthesis, viz. docosahexaenoic acid (DHA), eicosapentaenoic acid, uridine-mono-phosphate (UMP), choline, phospholipids, folic acid, vitamins B6, B12, C, E, and selenium. In order to …investigate whether the combined administration of these nutrients may also affect AD-like pathology, we now evaluated the effects of the FC diet intervention in the transgenic AβPPswe /PS1dE9 mouse model with endogenous Aβ production. In addition we evaluated the effects of diets containing the individual nutrients DHA and UMP and their combination in this model. Between the age of 3 and 6 months, FC diet decreased brain Aβ levels and amyloid plaque burden in the hippocampus of AβPP/PS1 mice. The FC diet also reduced ongoing disintegrative degeneration in the neocortex, as indicated by Amino Cupric Silver staining. Although all three DHA-containing diets were equally effective in changing brain fatty acid profiles, diets differentially affected amyloid-related measures, indicating that effects of DHA may depend on its dietary context. The current data, showing that dietary enrichment with FC reduces AD-like pathology in AβPP/PS1 mice, confirm and extend our previous findings in the Aβ42 infusion model and favor the combined administration of relevant nutrients. Show more

Keywords: AβPP/PS1 transgenic mice, Alzheimer's disease, amyloid-β, degenerative staining, DHA, Fortasyn Connect, nutrition, plaque burden, souvenaid, UMP

DOI: 10.3233/JAD-2012-112039

Citation: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 177-190, 2013

Authors: Rubial-Álvarez, Sandra | de Sola, Susana | Machado, María-Clara | Sintas, Elena | Böhm, Peter | Sánchez-Benavides, Gonzalo | Langohr, Klaus | Muñiz, Rubén | Peña-Casanova, Jordi

Article Type: Research Article

Abstract: The retrogenesis model states that the progression of brain aging and Alzheimer's disease (AD) deterioration proceeds inversely to human ontogenic acquisition patterns. Our aim was to assess if the progressive decline of cognitive abilities and functional capacity in AD follows an inverse sequence of acquisition compared to normal developmental patterns. One hundred eighty one children ranging in age from 4 to 12 years and 148 adults (cognitively normal, subjects with mild cognitive impairment, and mild-moderately severe AD) were assessed with the same cognitive and functional tools. The statistical analyses showed a progressive and inverse distribution on cognitive, functional, and mental …age scores when comparing results of children classified by chronological age and patients by dementia staging. The pattern of cognitive acquisition in children showed a progressive development of overall cognitive function along all age ranges, in addition to a simultaneous acquisition of instrumental and basic daily living activities in the functional domain. AD patients showed a progressive decline in cognitive and functional domains, which concurs with the sequence of impairment reported in this dementia. Our findings provide support to the inverse and progressive pattern of functional and cognitive decline observed in AD patients compared to the developmental acquisition of these capacities in children, as stated by the retrogenesis model. Nonetheless, certain differences should be considered when comparing the sequence of acquisition during ontogenic development with that of progressive loss during the course of AD. Retrogenesis may account for the progressive loss of neocortical-related functions in AD. Show more

Keywords: Activities of daily living, aging, Alzheimer's disease, child development, cognition, dementia

DOI: 10.3233/JAD-2012-121123

Citation: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 191-203, 2013