Journal of Alzheimer's Disease - Volume 28, issue 1

Authors: Chapuis, Julien | Vingtdeux, Valérie | Capiralla, Hemachander | Davies, Peter | Marambaud, Philippe

Article Type: Research Article

Abstract: The amyloid-β protein precursor (AβPP) is a type I transmembrane protein that undergoes maturation during trafficking in the secretory pathway. Proper maturation and trafficking of AβPP are necessary prerequisites for AβPP processing to generate amyloid-β (Aβ), the core component of Alzheimer's disease senile plaques. Recently, we reported that the glycosylphosphatidylinositol (GPI)-anchored protein growth arrest-specific 1 (Gas1) binds to and interferes with the maturation and processing of AβPP. Gas1 expression led to a trafficking blockade of AβPP between the endoplasmic reticulum (ER) and the Golgi. GPI-anchored proteins can exit the ER by transiting through raft subdomains acting as specialized sorting platforms. …Here, we show that Gas1 co-partitioned and formed a complex with AβPP in raft fractions, wherein Gas1 overexpression triggered immature AβPP accumulation. Pharmacological interference of ER to Golgi transport increased immature AβPP accumulation upon Gas1 expression in these raft fractions, which were found to be positive for the COPII protein complex component Sec31A, a specific marker for ER exit sites. Furthermore, a Gas1 mutant lacking the GPI anchor that could not transit through rafts was still able to form a complex with AβPP but did not lead to immature AβPP accumulation in rafts. Together these data show that Gas1 interfered with AβPP trafficking by interacting with AβPP to facilitate its translocation into specialized ER-associated rafts where immature AβPP accumulated. Show more

Keywords: AβPP, Alzheimer's disease, Gas1, lipid rafts, protein trafficking

DOI: 10.3233/JAD-2011-110434

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 127-135, 2012

Authors: Baker, Laura D. | Bayer-Carter, Jennifer L. | Skinner, Jeannine | Montine, Thomas J. | Cholerton, Brenna A. | Callaghan, Maureen | Leverenz, James B. | Walter, Brooke K. | Tsai, Elaine | Postupna, Nadia | Lampe, Johanna | Craft, Suzanne

Article Type: Research Article

Abstract: We previously showed that amyloid-β 1-42 (Aβ42 ) levels in cerebrospinal fluid (CSF) were markedly altered in response to a 4-week dietary intervention in normal aging and mild cognitive impairment (MCI). Here, we re-examined the data to assess whether diet-induced effects on CSF Aβ42 were modulated by high intensity physical activity (hi–PA). Normal older adults (n = 18, mean age = 68.6 ± 7.4 y) and adults with amnestic MCI (n = 23, mean age = 68.0 ± 6.5 y) received a low saturated fat/low glycemic index (LOW) diet or a high saturated fat/high glycemic index (HIGH) diet, and …CSF levels of Aβ42 , tau, and IL-8 were measured at baseline and week 4. Pre-study activity levels were assessed using a 7-d questionnaire, and weekly duration of hi–PA was quantified. At baseline, increased hi–PA in normals predicted lower CSF levels of tau (r = −0.54, p = 0.020) and IL-8 (r = −0.70, p = 0.025). Diet-induced effects on CSF Aβ42 during the intervention study were modulated by hi–PA, and the nature of this effect differed for normals and MCI (ANOVA, p = 0.039). That is, for normal adults, increased hi–PA attenuated the effects of the HIGH diet on CSF Aβ42 whereas in MCI, increased hi–PA potentiated the effects of the LOW diet. Our results suggest that normal adults who engage in hi–PA are less vulnerable to the pathological effects of an unhealthy diet, while in MCI, the benefit of a healthy diet on Aβ modulation is greatest when paired with hi–PA. Exercise may thus interact with diet to alter pathological processes that ultimately modify risk of Alzheimer's disease. Show more

Keywords: Aging, Alzheimer's disease, amyloid, biomarker, brain, diet, exercise, interleukin, mild cognitive impairment, tau

DOI: 10.3233/JAD-2011-111076

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 137-146, 2012

Authors: Gallagher, Joseph J. | Finnegan, Mary E. | Grehan, Belinda | Dobson, Jon | Collingwood, Joanna F. | Lynch, Marina A.

Article Type: Research Article

Abstract: There is a well-established literature indicating a relationship between iron in brain tissue and Alzheimer's disease (AD). More recently, it has become clear that AD is associated with neuroinflammatory and oxidative changes which probably result from microglial activation. In this study, we investigated the correlative changes in microglial activation, oxidative stress, and iron dysregulation in a mouse model of AD which exhibits early-stage amyloid deposition. Microfocus X-ray absorption spectroscopy analysis of intact brain tissue sections prepared from AβPP/PS1 transgenic mice revealed the presence of magnetite, a mixed-valence iron oxide, and local elevations in iron levels in tissue associated with amyloid-β-containing …plaques. The evidence indicates that the expression of markers of microglial activation, CD11b and CD68, and astrocytic activation, GFAP, were increased, and were histochemically determined to be adjacent to amyloid-β-containing plaques. These findings support the contention that, in addition to glial activation and oxidative stress, iron dysregulation is an early event in AD pathology. Show more

Keywords: Alzheimer's disease, iron, microglia, oxidative stress, spectrometry, X-ray fluorescence

DOI: 10.3233/JAD-2011-110614

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 147-161, 2012

Authors: Gustafson, Deborah R. | Bäckman, Kristoffer | Joas, Erik | Waern, Margda | Östling, Svante | Guo, Xinxin | Skoog, Ingmar

Article Type: Research Article

Abstract: Level of adiposity is linked to dementia in epidemiological studies. Overweight and obesity in mid- and late-life may increase risk for dementia, whereas decline in body weight or body mass index (BMI) and underweight in years preceding and at the time of a dementia diagnosis may also relate to dementia. Longitudinal studies with sufficient follow-up are necessary to estimate trajectories that allow better understanding of the relationship between adiposity indices and dementia over the life course. We evaluated the natural history of BMI in relationship to clinical dementia over 37 years in the Prospective Population Study of Women (PPSW) in …Sweden. PPSW is a systematic sample of 1462 women born 1908, 1914, 1918, 1922, and 1930 and aged 38–60 years at baseline. Examinations occurred in 1968, 1974, 1980, 1992, 2000, and 2005. Statistical analyses were conducted using mixed effects regression models. Trajectories of BMI over 37 years as a function of age differed between women who did versus did not develop dementia. Women developing dementia evidenced a lesser increase in BMI from age 38 to 70 years. After age 70, the BMI slope decreased similarly (no “accelerated decline”) irrespective of dementia status. A lower BMI before and during dementia onset was observed. Women with similar BMI at mid-life exhibited a different pattern of BMI change as they approached late-life that was related to dementia onset. BMI may be a potential marker of dementia-related neuropathologies in the brain. Dementia is related to a common risk factor, BMI, from mid-to late-life. Show more

Keywords: Alzheimer's disease, adiposity, body mass index, dementia, epidemiology, longitudinal, obesity, population-based, risk factor, women

DOI: 10.3233/JAD-2011-110917

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 163-171, 2012

Authors: Elipenahli, Ceyhan | Stack, Cliona | Jainuddin, Shari | Gerges, Meri | Yang, Lichuan | Starkov, Anatoly | Beal, M. Flint | Dumont, Magali

Article Type: Research Article

Abstract: Coenzyme Q10 is a key component of the electron transport chain which plays an essential role in ATP production and also has antioxidant effects. Neuroprotective effects of coenzyme Q10 have been reported in both in vitro and in vivo models of neurodegenerative diseases. However, its effects have not been studied in cells or in animals with tau induced pathology. In this report, we administered coenzyme Q10 to transgenic mice with the P301S tau mutation, which causes fronto-temporal dementia in man. These mice develop tau hyperphosphorylation and neurofibrillary tangles in the brain. Coenzyme Q10 improved survival and behavioral deficits in the …P301S mice. There was a modest reduction in phosphorylated tau in the cortex of P301S mice. We also examined the effects of coenzyme Q10 treatment on the electron transport chain enzymes, the mitochondrial antioxidant enzymes, and the tricarboxylic acid cycle. There was a significant increase in complex I activity and protein levels, and a reduction in lipid peroxidation. Our data show that coenzyme Q10 significantly improved behavioral deficits and survival in transgenic mice with the P301S tau mutation, upregulated key enzymes of the electron transport chain, and reduced oxidative stress. Show more

Keywords: Coenzyme Q10, mitochondria, tauopathy, transgenic mice

DOI: 10.3233/JAD-2011-111190

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 173-182, 2012

Authors: Kaneai, Nozomi | Arai, Masaya | Takatsu, Hirokatsu | Fukui, Koji | Urano, Shiro

Article Type: Research Article

Abstract: One characteristic of age-related neurodegeneration is thought to be cognitive deficits caused by oxidative stress. Neurons in the brain are considered to be particularly vulnerable to oxidative stress, leading to neuronal oxidative damage and neurodegenerative disorders such as Alzheimer's disease (AD) and senile dementia. The process of fusing synaptic plasma membranes and synaptic vesicles involves particular proteins, such as the soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein receptor (SNARE) proteins for docking both membranes, and is integral to neurotransmission. To elucidate whether oxidative stress induces denaturation of SNARE proteins, and whether vitamin E can counteract this process, changes in the expression …of synaptobrevin, synaptotagmin, SNAP-25, and syntaxin-1 in rat brain nerve terminals were analyzed using an immunoblotting method. The results showed that oxidative stress induced significant reductions in the levels synaptobrevin and synaptotagmin in synaptic vesicles. Similarly, marked decreases in the levels of SNAP-25 and syntaxin-1 in pre-synaptic plasma membranes were also observed. In the absence of oxidative stress, vitamin E-deficient rats exhibited similar decreases in these proteins. In contrast, it was found that decreases in SNARE proteins, except for SNAP-25, were not observed in vitamin E-supplemented rats, even when the rats were subjected to oxidative stress. These results suggest that reactive oxygen species generated by oxidative stress are detrimental to neurons, resulting in the oxidation of SNARE proteins, thereby disrupting neurotransmission. Additionally, vitamin E is capable of protecting against such neurodegeneration. Show more

Keywords: Neurotransmission, oxidative stress, SNARE protein, synaptic membrane fusion, vitamin E

DOI: 10.3233/JAD-2011-111133

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 183-189, 2012

Authors: Hooijmans, Carlijn R. | Pasker-de Jong, Pieternel C.M. | de Vries, Rob B.M. | Ritskes-Hoitinga, Merel

Article Type: Research Article

Abstract: To date, only a few randomized clinical trials (RCTs) have investigated the effects of omega-3 fatty acids (FA) on Alzheimer's disease (AD). Some of these studies demonstrated that patients with very mild AD or mild cognitive impairment benefit from omega-3 FA treatment, but none showed significant improvements in cognitive function in patients with moderate or advanced AD. All these RCTs had a relatively short duration of supplementation, however, and we hypothesized that this might be one of the reasons why no effects of omega-3 FA supplementation could be observed in patients with “moderate” or “advanced” AD. Animal studies offer better …possibilities for controlled long-term supplementation than clinical studies. Therefore, we performed a systematic review (SR) and meta-analysis of the literature that focused on effects of the relatively long-term omega-3 FA supplementation (minimum period; 10% of average total lifespan) on cognitive impairment, amyloid-β pathology, and neuronal loss in animal models of AD. This SR shows that long-term omega-3 FA supplementation decreased the omega-6/omega-3 FA ratio and reduced the amount of amyloid-β in experimental animal models of AD. Omega-3 FA supplementation also improved cognitive function; this effect appeared larger in rats compared to mice, and in males compared to females. Moreover, omega-3 FA supplementation diminished the amount of neuronal loss, especially in female animals. The results of this SR indicate that it might be worthwhile to perform new clinical trials with long-term omega-3 FA supplementation in AD patients. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, animal models, cognition, docosahexaenoic acid, omega-3 fatty acids, pathology, systematic review

DOI: 10.3233/JAD-2011-111217

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 191-209, 2012

Authors: Olazarán, Javier | Agüera-Ortiz, Luis | Osorio, Ricardo S. | León-Salas, Beatriz | Dobato, José Luis | Cruz-Orduña, Isabel | González, Belén | Valentí, Meritxell | Gil-Ruiz, Nuria | Frades, Belén | Ramos-García, M.I. | Martínez-Martín, Pablo

Article Type: Research Article

Abstract: The Alzheimer Center Reina Sofía Foundation (ACRSF) was envisaged to address the complex and multi-disciplinary research and care needs posed by Alzheimer's disease (AD) and other neurodegenerative dementias. Patients may be admitted at ACRSF either as inpatients (i.e., nursing home) or outpatients (i.e., day-care center). The research program includes clinical, social, biochemical, genetic, and magnetic resonance investigations, as well as brain donation. We present the inception of the clinical research protocol for the ACRSF, the early results, and the amendments to the protocol. Foreseen as distinct populations, inpatient and outpatient results are presented separately. Data were collected from 180 patients …(153 inpatients, 27 outpatients) (86% AD), with informed consent for participation in the research program of the ACRSF. Most patients (95%) had moderate to severe dementia. Nursing home patients were older, displayed marked gait dysfunction, and were significantly more dependent in the activities of daily living (ADL), compared to the day-care patients (p < 0.05). Some cognitive, ADL, and quality of life (QoL) scales were eliminated from the protocol due to floor effect or lack of specificity of contents for advanced dementia. New measurements were added for evaluation of cognition, apathy, agitation, depression, ADL, motor function, and QoL. The final assessment is expected to be sensitive to change in all the clinical aspects of advanced degenerative dementia, to promote multidisciplinary and, desirably, inter-center collaborative research and, eventually, to contribute to the improvement of treatment and care for these patients. Show more

Keywords: Alzheimer's disease, clinical research protocol, geriatric assessment, inpatients, nursing homes, outpatients, primary senile degenerative dementia

DOI: 10.3233/JAD-2011-110875

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 211-222, 2012

Authors: Marioni, Riccardo E. | van den Hout, Ardo | Valenzuela, Michael J. | Brayne, Carol | Matthews, Fiona E. | MRC Cognitive Function and Ageing Study

Article Type: Research Article

Abstract: Education and lifestyle factors linked with complex mental activity are thought to affect the progression of cognitive decline. Collectively, these factors can be combined to create a cognitive reserve or cognitive lifestyle score. This study tested the association between cognitive lifestyle score and cognitive change in a population-based cohort of older persons from five sites across England and Wales. Data came from 13,004 participants of the Medical Research Council Cognitive Function and Ageing Study who were aged 65 years and over. Cognition was assessed at multiple waves over 16 years using the Mini-Mental State Examination. Subjects were grouped into four …cognitive states (no impairment, slight impairment, moderate impairment, severe impairment) and cognitive lifestyle score was assessed as a composite measure of education, mid-life occupation, and current social engagement. A multi-state model was used to test the effect of cognitive lifestyle score on cognitive transitions. Hazard ratios for cognitive lifestyle score showed significant differences between those in the upper compared to the lower tertile with a more active cognitive lifestyle associating with: a decreased risk of moving from no to slight impairment (0.58, 95% CI (0.45, 0.74)); recovery from a slightly impaired state back to a non-impaired state (2.93 (1.35, 6.38)); but an increased mortality risk from a severely impaired state (1.28 (1.12, 1.45)). An active cognitive lifestyle is associated with a more favorable cognitive trajectory in older persons. Future studies would ideally incorporate neuroradiological and neuropathological data to determine if there is causal evidence for these associations. Show more

Keywords: All epidemiology, cognitive aging, cognitive reserve, education

DOI: 10.3233/JAD-2011-110377

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 223-230, 2012

Authors: Hansson, Oskar | Stomrud, Erik | Vanmechelen, Eugeen | Östling, Svante | Gustafson, Deborah R | Zetterberg, Henrik | Blennow, Kaj | Skoog, Ingmar

Article Type: Research Article

Abstract: Amyloid-β (Aβ) pathology is a major component in the mechanisms behind Alzheimer's disease (AD). Measurement of Aβ42 in cerebrospinal fluid predicts cognitive decline in patients with mild cognitive impairment and identifies AD in patients with dementia. However, studies on Aβ in plasma are contradictory. In this prospective population-based study, plasma Aβ42 and Aβ40 were measured at baseline in 730 adults aged 70 years or older and without dementia. After five years, plasma levels were analyzed again and participants were assessed for development of dementia. During follow-up, 53 individuals (7%) developed dementia of which 37 (5%) were classified …as AD. No difference in baseline plasma Aβ42 , Aβ40 , or Aβ42 /Aβ40 ratio levels were observed between converters to dementia or AD compared to the cognitively stable individuals. However, individuals with plasma Aβ40 levels above the median level for the group at baseline had an increased risk of developing dementia and AD during the follow-up, even after adjustment for age, gender, APOE genotype, and educational level (odds ratio = 2.2, 95% confidence interval = 1.0–4.7, p < 0.05). Neither plasma Aβ42 nor the Aβ42 /Aβ40 ratio influenced the risk of developing dementia or AD. Moreover, Aβ42 and Aβ40 levels increased over the 5 years, whereas the Aβ42 /Aβ40 ratio decreased (p < 0.001). In conclusion, this study suggests that measurement of plasma Aβ should not be used clinically to predict dementia or AD. However, plasma Aβ40 may possibly be regarded as a moderate risk marker comparable to other risk markers for AD such as first-degree family history of dementia. Show more

Keywords: Alzheimer's disease, amyloid-β 40, amyloid-β 42, biological markers, cohort studies, dementia, plasma

DOI: 10.3233/JAD-2011-111418

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 231-238, 2012

Article Type: Other

DOI: 10.3233/JAD-2011-111419

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 239-240, 2012