Journal of Alzheimer's Disease - Volume 33, issue 4

Authors: Lu, Jianghua | E, Lezi | Roy, Nairita | Hutfles, Lewis | Selfridge, Eva | Funk, Eric | Burns, Jeffrey M. | Swerdlow, Russell H.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) patients have reduced brain acetylcholine and reversing this deficit yields clinical benefits. In this study we explored how increased cholinergic tone impacts cell bioenergetics, which are also perturbed in AD. We treated SH-SY5Y neuroblastoma cells with carbachol, a cholinergic agonist, and tested for bioenergetic flux and bioenergetic infrastructure changes. Carbachol rapidly increased both oxidative phosphorylation and glycolysis fluxes. ATP levels rose slightly, as did cell energy demand, and AMPK phosphorylation occurred. At least some of these effects depended on muscarinic receptor activation, ER calcium release, and ER calcium re-uptake. Our data show that increasing cholinergic signaling enhances …cell bioenergetics, and reveal mechanisms that mediate this effect. Phenomena we observed could potentially explain why cholinesterase inhibitor therapy increases AD brain glucose utilization and N-acetyl aspartate levels. The question of whether cholinesterase inhibitors have a disease modifying effect in AD has long been debated; our data suggest a theoretical mechanism through which such an effect could potentially arise. Show more

Keywords: Acetylcholine, Alzheimer's disease, bioenergetics, carbachol, glycolysis, mitochondria

DOI: 10.3233/JAD-2012-121822

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1135-1146, 2013

Authors: Wang, Jun | Wright, Harold M. | Vempati, Prashant | Li, Henry | Wangsa, Julie | Dzhuan, Anastasiya | Habbu, Karishma | Knable, Lindsay A. | Ho, Lap | Pasinetti, Giulio M.

Article Type: Research Article

Abstract: Nebivolol is a selective β1 adrenergic receptor antagonist with nitric oxide-mediated vasodilatory properties utilized in the treatment of hypertension. Previously, nebivolol was shown to modulate amyloid-β protein precursor processing in vitro. In this study, we investigated the in vivo effects of nebivolol on the modulation of amyloid neuropathology in the Tg2576 mouse model of Alzheimer's disease (AD). We found that nebivolol is brain bioavailable and can be readily detected in the brain following three weeks of treatment at a dose of 1 mg/kg/day. Moreover, this treatment regime resulted in a significant reduction of amyloid-β neuropathology in the brain, and this …reduction was inversely correlated with plasma levels of amyloid-β. Chronic nebivolol treatment of Tg2576 mice with established amyloid neuropathology and cognitive impairments significantly reduced brain amyloid content but failed to improve cognitive function. Our study demonstrates that nebivolol is highly tolerable and safe and can significantly reduce amyloid neuropathology in the brain, which could be one of the most important parameters for primary prevention of AD. Our studies support the continued investigation of nebivolol for the treatment of AD at very early stages of the disease. Show more

Keywords: Adrenergic receptor blocker, Alzheimer's disease, brain bioavailability, inflammatory response, plaque

DOI: 10.3233/JAD-2012-120904

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1147-1156, 2013

Authors: Serra, Laura | Giulietti, Giovanni | Cercignani, Mara | Spanò, Barbara | Torso, Mario | Castelli, Diana | Perri, Roberta | Fadda, Lucia | Marra, Camillo | Caltagirone, Carlo | Bozzali, Marco

Article Type: Research Article

Abstract: This study investigates whether different patterns of grey matter (GM) loss may account for the different neuropsychological profiles observed in patients with amnestic (a-) and non-amnestic (na-) mild cognitive impairment (MCI), and may predict patients' clinical evolution. Fifty-five consecutive individuals complaining of cognitive dysfunction (referred to specialist dementia clinics) were screened and included in the study if they met the diagnostic criteria for MCI on a neurodegenerative basis. After an extensive neuropsychological assessment, patients were classified as suffering from a-MCI or na-MCI. Twenty-eight healthy individuals were also recruited and served as controls. All participants underwent magnetic resonance imaging at 3T, …including conventional images and volumetric scans. Volumetric data were processed using voxel-based morphometry to assess between-group differences in regional GM volumes and correlations with neuropsychological performances. When compared to controls, a-MCI patients showed prominent GM volume reductions in the medial temporal lobes, while those with na-MCI showed reduced GM volumes in the orbito-frontal cortex and basal ganglia. In a-MCI patients, significant associations were found between verbal long-term memory performance and GM volumes in the hippocampus. Conversely, in na-MCI patients, associations were found between scores at tests exploring executive functions and GM volumes in the orbito-frontal cortex. At one-year follow-up, conversions were recorded exclusively toward Alzheimer's disease (AD) in the a-MCI group, and toward non-AD dementia in the na-MCI group. This study confirms that MCI is a heterogeneous clinical identity including different neurodegenerative entities; specific patterns of regional GM loss appear to account for specific neuropsychological features and are likely to predict patients' clinical evolution. Show more

Keywords: Alzheimer's disease, amnestic mild cognitive impairment, magnetic resonance imaging, non-amnestic mild cognitive impairment, voxel-based morphometry

DOI: 10.3233/JAD-2012-121663

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1157-1165, 2013

Authors: Lim, Yen Ying | Ellis, Kathryn A. | Harrington, Karra | Pietrzak, Robert H. | Gale, Joanne | Ames, David | Bush, Ashley I. | Darby, David | Martins, Ralph N. | Masters, Colin L. | Rowe, Christopher C. | Savage, Greg | Szoeke, Cassandra | Villemagne, Victor L. | Maruff, Paul | For the AIBL Research Group

Article Type: Research Article

Abstract: We aimed to characterize the nature and magnitude of cognitive decline in a group of adults with amnestic mild cognitive impairment (aMCI) with high and low levels of amyloid-β (Aβ) in relation to healthy older adults with low Aβ levels. Healthy older adults and adults with aMCI enrolled in the Australian Imaging, Biomarker, and Lifestyle study, completed the CogState brief battery at baseline and 18 months, and underwent positron emission tomography neuroimaging for Aβ at baseline. In this study, we included adults with MCI who had been classified as having high and low levels of Aβ and healthy older adults …who had been classified as having low levels of Aβ. Linear model analyses adjusted for baseline cognitive function indicated that relative to healthy older adults with low Aβ, adults with aMCI and high Aβ showed greater decline in working memory and in verbal and visual episodic memory at 18 months. Adults with aMCI and low Aβ also showed greater decline in working memory; however they did not evidence any decline in episodic memory at 18 months. The results of our study suggests that relative to healthy older adults and adults with aMCI with low Aβ, adults with aMCI and high levels of Aβ showed faster rates of decline on measures of episodic memory over 18 months, and this was approximately twice that observed previously for healthy older adults with high Aβ levels. Show more

Keywords: Alzheimer's disease, amyloid-β, cognitive change, cognitive neuropsychology, mild cognitive impairment

DOI: 10.3233/JAD-121771

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1167-1176, 2013

Authors: Alvarez-López, María Jesús | Castro-Freire, Marco | Cosín-Tomás, Marta | Sanchez-Roige, Sandra | Lalanza, Jaume F. | del Valle, Jaume | Párrizas, Marcelina | Camins, Antonio | Pallás, Merce | Escorihuela, Rosa María | Kaliman, Perla

Article Type: Research Article

Abstract: The senescence-accelerated SAMP8 mouse is considered a useful non-transgenic model for studying aspects of progressive cognitive decline and Alzheimer's disease (AD). Using SAMR1 mice as controls, here we explored the effects of 6 months of voluntary wheel running in 10-month-old female SAMP8 mice. Exercise in SAMP8 mice improved phenotypic features associated with premature aging (i.e., skin color and body tremor) and enhanced vascularization and BDNF gene expression in the hippocampus compared with controls. With the aim of identifying genes involved in brain aging responsive to long-term exercise, we performed whole genome microarray studies in hippocampus from sedentary SAMP8 (P8sed), SAMR1 …(R1sed), and exercised SAMP8 (P8run) mice. The genes differentially expressed in P8sed versus R1sed were considered as putative aging markers (i) and those differentially expressed in P8run versus P8sed were considered as genes modulated by exercise (ii). Genes differentially expressed in both comparisons (i and ii) were considered as putative aging genes responsive to physical exercise. We identified 34 genes which met both criteria. Gene ontology analysis revealed that they are mainly involved in functions related to extracellular matrix maintenance. Selected genes were validated by real-time quantitative PCR assays, i.e., collagen type 1 alpha 1 (col1a1), collagen type 1 alpha 2 (col1a2), fibromodulin (fmod), prostaglandin D(2) synthase (ptgds), and aldehyde dehydrogenase (Aldh1a2). As a whole, our study suggests that exercise training during adulthood may prevent or delay gene expression alterations and processes associated with hippocampal aging in at-risk subjects. Show more

Keywords: Aging, Alzheimer's disease, brain, exercise, gene, long-term, mice, microarrays, SAMP8, voluntary

DOI: 10.3233/JAD-121264

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1177-1190, 2013

Authors: Ashford, J. Wesson | Bayley, Peter J.

Article Type: Article Commentary

DOI: 10.3233/JAD-2012-121124

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1191-1193, 2013

Article Type: Other

DOI: 10.3233/JAD-121265

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1195-1196, 2013

Article Type: Other

DOI: 10.3233/JAD-33428

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1197-1208, 2013