Journal of Alzheimer's Disease - Volume 44, issue 1

Authors: Chang, Kai Lun | Pee, Hai Ning | Tan, Wee Pin | Dawe, Gavin S. | Holmes, Elaine | Nicholson, Jeremy K. | Chan, Eric C.Y. | Ho, Paul C.

Article Type: Research Article

Abstract: In this study, we performed gas chromatography time-of-flight mass spectrometry (GC-TOFMS)-based extracellular metabolic profiling on AβPP-transfected CHO cells (CHO-AβPP695 ) and its wildtype. Orthogonal partial least squares discriminant analysis (OPLS-DA) was then used to identify discriminant metabolites, which gave clues on the effects of AβPP transgene on cellular processes. To confirm the hypotheses generated based on the metabolic data, we performed biochemical assays to gather further evidence to support our findings. The OPLS-DA showed a robust differentiation following 24 h of incubation (Q2 (cum) = 0.884) and 15 discriminant metabolites were identified. In contrast, extracellular Aβ42 was identified to …increase significantly in CHO-AβPP695 only after incubation for 48 h. The observed 24-h metabolic fluxes were associated with increased mitochondrial AβPP and reduced mitochondrial viabilities, which occurred before extracellular Aβ accumulation. We also investigated the therapeutic potential of peroxisome proliferator-activated receptor gamma (PPARγ) agonists, namely rosiglitazone (RSG) and pioglitazone (PIO), by employing the same approach to characterize the metabolic profiles of CHO-AβPP695 treated with RSG and PIO, with or without their respective receptor blockers. Treatment with PIO was found to reduce the perturbation of the discriminant metabolites in CHO-AβPP695 to a larger extent than treatment with RSG. We also attributed the PIO effects on the lowering of Aβ42 , and restoration of mitochondrial activity to PPARγ and PPARα agonism, respectively. Taken together, PIO was demonstrated to be therapeutically superior to RSG. Our findings provide further insights into early disease stages in this AβPP model, and support the advancement of PIO in AD therapy. Show more

Keywords: Alzheimer's disease, amyloid beta-protein precursor (AβPP), metabolomics, metabonomics, mitochondria, pioglitazone, rosiglitazone

DOI: 10.3233/JAD-140429

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 215-231, 2015

Authors: Woodward, Michael C. | Rowe, Christopher C. | Jones, Gareth | Villemagne, Victor L. | Varos, Tammie A.

Article Type: Research Article

Abstract: Background: Alzheimer's disease (AD) can present with behavioral changes with this syndrome described as frontal variant AD (FvAD). Excess frontal pathology may explain this presentation. Neuroimaging with fluoro-deoxy-glucose positron emission tomography (FDG- PET) can be used to examine the effects of pathology in FvAD. Methods: We administered an assessment scale for frontal behavioral impairment, the Frontal Behavioral Inventory (FBI), to 53 patients with AD. Scores in the top quartile were defined as FvAD. FDG- PET was analyzed in 8 frontal regions. Results: The Z (SD) score for metabolism was significantly higher (indicating greater hypometabolism) in the …FvAD group than the remaining AD group for combined left and right orbitofrontal regions (2.64 (SD 0.99) versus 2.11 (1.22), p < 0.03)) and combined left and right medial frontal regions (2.38 (0.63) versus 1.82 (0.88) p < 0.003) but insignificantly different in combined lateral frontal and superior frontal regions. Statistical parametric mapping revealed these frontal regions to be the only brain regions with significantly different metabolism between the FvAD and the remainder of the AD groups. Conclusions: Medial and orbital frontal hypometabolism is greater in AD patients presenting with more frontal/behavioral features, likely reflecting a greater pathological load in these brain regions in FvAD patients. These frontal regions may be more linked to behavioral features than other frontal brain regions. Show more

Keywords: Alzheimer's disease, behavioral features versus hypometabolism, degree of hypometabolism, Frontal Behavioral Inventory, frontal variant Alzheimer's disease, FDG- PET, statistical parametric mapping

DOI: 10.3233/JAD-141110

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 233-242, 2015

Authors: Bozzali, Marco | Dowling, Claire | Serra, Laura | Spanò, Barbara | Torso, Mario | Marra, Camillo | Castelli, Diana | Dowell, Nicholas G. | Koch, Giacomo | Caltagirone, Carlo | Cercignani, Mara

Article Type: Research Article

Abstract: One factor believed to impact brain resilience to the pathological damage of Alzheimer's disease (AD) is the so-called “cognitive reserve” (CR). A critical issue that still needs to be fully understood is the mechanism by which environmental enrichment interacts with brain plasticity to determine resilience to AD pathology. Previous work using PET suggests that increased brain connectivity might be at the origin of the compensatory mechanisms implicated in this process. This study aims to further clarify this issue using resting-state functional MRI. Resting-state functional MRI was collected for 11 patients with AD, 18 with mild cognitive impairment (MCI), and 16 …healthy controls, and analyzed to isolate the default mode network (DMN). A quantitative score of CR was obtained by combining information about number of years of education and type of schools attended. Consistent with previous reports, education was found to modulate functional connectivity in the posterior cingulate cortex, whose disconnection with the temporal lobes is known to be critical for the conversion from MCI to AD. This effect was highly significant in AD patients, less so in patients with MCI, and absent in healthy subjects. These findings show the potential neural mechanisms underlying the individual's ability to cope with brain damage, although they should be treated with some caution based on small numbers. Show more

Keywords: Alzheimer's disease, cognitive reserve, mild cognitive impairment, resting-state functional MRI

DOI: 10.3233/JAD-141824

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 243-250, 2015

Authors: Liu, Xia | Ye, Keqiang | Weinshenker, David

Article Type: Research Article

Abstract: The locus coeruleus (LC), the brainstem noradrenergic nucleus that is the sole source of norepinephrine (NE) in the forebrain, is one of the first structures affected in Alzheimer's disease (AD). Experimental ablation of the LC exacerbates, while increasing NE abates, AD-like neuropathology and cognitive deficits in animal models of the disease. Some neuroprotective effects of NE appear to be mediated by tropomyosin-related kinase B (TrkB), the canonical receptor for brain-derived neurotrophic factor (BDNF). Here, we report that NE dose-dependently protected primary cortical and LC neurons from amyloid-β (Aβ) toxicity. The neuroprotective effects of NE were fully prevented by the Trk …receptor antagonist K252a but only partially attenuated by adrenergic receptor antagonists and not mimicked by adrenergic agonists. Activation of TrkB by NE in cortical and LC neurons was confirmed by immunoblot and immunocytochemistry for phospho-TrkB. These results indicate that NE can activate TrkB and protect against Aβ toxicity, at least in part, via adrenergic receptor-independent mechanisms, and have implications for the consequences of LC degeneration in AD and potential therapies for the disease. Show more

Keywords: Alzheimer's disease, amyloid-β, brain-derived neurotrophic factor, locus coeruleus, neuroprotection, norepinephrine, tropomyosin-related kinase B

DOI: 10.3233/JAD-141062

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 251-260, 2015

Authors: Chun, Yoon Sun | Park, Yurim | Oh, Hyun Geun | Kim, Tae-Wan | Yang, Hyun Ok | Park, Myoung Kyu | Chung, Sungkwon

Article Type: Research Article

Abstract: Amyloid-β protein precursor (AβPP) is transported to the plasma membrane, where it is sequentially cleaved by α-secretase and γ-secretase. This is called non-amyloidogenic pathway since it precludes the production of amyloid-β (Aβ), the main culprit of Alzheimer's disease (AD). Alternatively, once AβPP undergoes clathrin-dependent endocytosis, it can be sequentially cleaved by β-secretase and γ-secretase at endosomes, producing Aβ (amyloidogenic pathway). β-N-acetylglucosamine (GlcNAc) can be attached to serine/threonine residues of the target proteins. This novel type of O-linked glycosylation is called O-GlcNAcylation mediated by O-GlcNAc transferase (OGT). The removal of GlcNAc is mediated by O-GlcNAcase (OGN). Recently, it is shown that …O-GlcNAcylation of AβPP increases the non-amyloidogenic pathway. To investigate the regulatory role for O-GlcNAcylation in AβPP processing, we first tested the effects of inhibitor for OGN, PUGNAc, on AβPP metabolism in HeLa cells stably transfected with Swedish mutant form of AβPP. Increasing O-GlcNAcylated AβPP level increased α-secretase product while decreased β-secretase products. We found that PUGNAc increased the trafficking rate of AβPP from the trans-Golgi network to the plasma membrane, and selectively decreased the endocytosis rate of AβPP. These events may contribute to the increased AβPP level in the plasma membrane by PUGNAc. Inhibiting clathrin-dependent endocytosis prevented the effect of PUGNAc on Aβ, suggesting that the effect of PUGNAc was mainly mediated by decreasing AβPP endocytosis. These results strongly indicate that O-GlcNAcylation promotes the plasma membrane localization of AβPP, which enhances the non-amyloidogenic processing of AβPP. Thus, O-GlcNAcylation of AβPP can be a potential therapeutic strategy for AD. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, endocytosis, O-GlcNAcylation

DOI: 10.3233/JAD-140096

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 261-275, 2015

Authors: Calvi, Alberto | Cioffi, Sara M.G. | Caffarra, Paolo | Fenoglio, Chiara | Serpente, Maria | Pietroboni, Anna M. | Arighi, Andrea | Ghezzi, Laura | Gardini, Simona | Scarpini, Elio | Galimberti, Daniela

Article Type: Research Article

Abstract: Mutations in progranulin gene (GRN) are a common cause of autosomal dominant frontotemporal lobar degeneration and are associated with a wide phenotypic heterogeneity. Here, we describe two probands with behavioral variant frontotemporal dementia with a novel mutation in this gene (1159_1160delTG). Both had a positive family history for dementia and showed atypical features at imaging. Their progranulin plasma levels were undetectable, and the mutation was not present in cDNA, suggesting haploinsufficiency. Progranulin levels were low even in asymptomatic carriers of the variant. Results described enlarge current knowledge on genetic causes of the disease and clinical characteristics of carriers.

Keywords: Deletion, frontotemporal dementia, haploinsufficiency, mutation, progranulin (GRN)

DOI: 10.3233/JAD-141380

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 277-282, 2015

Authors: McClure, Richard | Yanagisawa, Daijiro | Stec, Donald | Abdollahian, Dave | Koktysh, Dmitry | Xhillari, Dritan | Jaeger, Rudolph | Stanwood, Gregg | Chekmenev, Eduard | Tooyama, Ikuo | Gore, John C. | Pham, Wellington

Article Type: Research Article

Abstract: Curcumin is a promising compound that can be used as a theranostic agent to aid research in Alzheimer's disease. Beyond its ability to bind to amyloid plaques, the compound can also cross the blood-brain barrier. Presently, curcumin can be applied only to animal models, as the formulation needed for iv injection renders it unfit for human use. Here, we describe a novel technique to aerosolize a curcumin derivative, FMeC1, and facilitate its safe delivery to the brain. Aside from the translational applicability of this approach, a study in the 5XFAD mouse model suggested that inhalation exposure to an aerosolized FMeC1 …modestly improved the distribution of the compound in the brain. Additionally, immunohistochemistry data confirms that following aerosol delivery, FMeC1 binds amyloid plaques expressed in the hippocampal areas and cortex. Show more

Keywords: Aerosol, Alzheimer's disease, amyloid imaging, amyloid plaques, atomization, inhalation exposure, clinical translation, curcumin

DOI: 10.3233/JAD-140798

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 283-295, 2015

Authors: Kawada, Hiroyoshi | Blessing, Karen | Kiyota, Tomomi | Woolman, Theodor | Winchester, Lee | Kador, Peter F.

Article Type: Research Article

Abstract: Background: Redox-active metal dyshomeostasis and oxidative stress are associated with mitochondrial dysfunction and amyloid-β (Aβ) neurotoxicity that are linked to both the development of age-related macular degeneration (AMD) and Alzheimer's disease (AD). As potential therapeutic agents, orally active multifunctional antioxidants (MFAOs) possessing two independent functional groups capable of binding redox-active metals and scavenging free radicals have been synthesized. Objective: To determine whether MFAOs affect mitochondrial function and reduce the presence of Aβ plaque formation. Methods: The MFAOs were evaluated in cultured SH-SY5Y cells and ARPE-19 cells. MFAO effects on mitochondrial function were investigated using rhodamine 123 …staining after 2 hour exposure to MnCl2 . MFAO effects on Aβ:Zn complex formation were evaluated with Zinquin staining and the ability of the Aβ:Zn complex to be degraded by matrix metalloproteinase-2 (MMP-2). The ability of MFAOs to reduce Aβ plaque in the brain was determined by orally feeding MFAO for one year to B6;129-Psen1tm1Mpm Tg(AβPPSwe,tauP301L) 1Lfa/Mmjax transgenic mice. Aβ levels were determined by ELISA. Results: MFAOs neither adversely affected mitochondrial signaling nor labile cytoplasmic zinc levels. MFAOs protected cells against Mn2+ -induced mitochondrial dysfunction. MFAOs also removed zinc from the Aβ:Zn complex so that Aβ plaque could be degraded by MMP-2. Zinquin staining indicated that the removed zinc was present in the cytoplasm as labile zinc. Orally administered MFAOs reduced the brain levels of both Aβ40 and Aβ42 isoforms of Aβ. Conclusion: These studies demonstrate that these MFAOs have metal attenuating properties with therapeutic potential in the treatment of both AMD and AD. Show more

Keywords: Age-related macular degeneration, Alzheimer's disease, amyloid-β, clioquinol, JAX transgenic Alzheimer mouse, mitochondrial dysfunction, multifunctional antioxidants

DOI: 10.3233/JAD-132471

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 297-307, 2015

Authors: Gifford, Katherine A. | Liu, Dandan | Damon, Stephen M. | Chapman IV, William G. | Romano III, Raymond R. | Samuels, Lauren R. | Lu, Zengqi | Jefferson, Angela L. | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: A cognitive concern from the patient, informant, or clinician is required for the diagnosis of mild cognitive impairment (MCI); however, the cognitive and neuroanatomical correlates of complaint are poorly understood. Objective: We assessed how self-complaint relates to cognitive and neuroimaging measures in older adults with MCI. Method: MCI participants were drawn from the Alzheimer's Disease Neuroimaging Initiative and dichotomized into two groups based on the presence of self-reported memory complaint (no complaint n = 191, 77 ± 7 years; complaint n = 206, 73 ± 8 years). Cognitive outcomes included episodic memory, executive functioning, information …processing speed, and language. Imaging outcomes included regional lobar volumes (frontal, parietal, temporal, cingulate) and specific medial temporal lobe structures (hippocampal volume, entorhinal cortex thickness, parahippocampal gyrus thickness). Results: Linear regressions, adjusting for age, gender, race, education, Mini-Mental State Examination score, mood, and apolipoprotein E4 status, found that cognitive complaint related to immediate (β = −1.07, p < 0.001) and delayed episodic memory performances assessed on a serial list learning task (β = −1.06, p = 0.001) but no other cognitive measures or neuroimaging markers. Conclusions: Self-reported memory concern was unrelated to structural neuroimaging markers of atrophy and measures of information processing speed, executive functioning, or language. In contrast, subjective memory complaint related to objective verbal episodic learning performance. Future research is warranted to better understand the relation between cognitive complaint and surrogate markers of abnormal brain aging, including Alzheimer's disease, across the cognitive aging spectrum. Show more

Keywords: Alzheimer's disease, cognitive complaint, episodic memory, magnetic resonance imaging, mild cognitive impairment, serial list-learning

DOI: 10.3233/JAD-140636

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 309-318, 2015

Authors: Riverol, Mario | Becker, James T. | López, Oscar L. | Raji, Cyrus A. | Thompson, Paul M. | Carmichael, Owen T. | Gach, H. Michael | Longstreth Jr., William T. | Fried, Linda | Tracy, Russell P. | Kuller, Lewis H.

Article Type: Research Article

Abstract: Cerebral white matter lesions (WMLs) are considered a reflection of cerebral and systemic small vessel disease (SVD), and are associated with reductions in brain volume. Like the brain, the kidney is also sensitive to factors that affect vasculature. Glomerular dysfunction due to renal vascular damage can be measured with different biochemical parameters, such as creatinine or cystatin C, although cystatin C is considered to be more accurate than creatinine in the elderly. The purpose of the study was to determine whether manifestations of SVD in the kidney can predict SVD-based damage to the brain. We examined the relationship between glomerular …dysfunction as a measure of SVD on WMLs, gray matter (GM) volume, and cognition in 735 cognitively normal participants from the Cardiovascular Health Study Cognition Study. The multivariate analyses controlled for demographic characteristics, hypertension, heart disease, diabetes, Apolipoprotein 4 allele, C reactive protein, lipids, physical activity, smoking, and body mass index (BMI). Elevated cystatin C levels were associated with lower neuropsychological test scores, the presence of MRI-identified brain infarcts, the severity of WMLs, and GM atrophy five years later. In adjusted models, GM volume was significantly associated with cystatin-C only until BMI and severity of WMLs were added to the model, meaning that the effect of SVD on GM volume is mediated by these two variables. These findings suggest that age-related SVD is a process that leads to altered brain structure, and creates a vulnerability state for cognitive decline. Show more

Keywords: Cognitive impairment, cystatin C, gray matter volume, white matter lesions

DOI: 10.3233/JAD-141077

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 319-328, 2015