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The Journal of Alzheimer’s Disease is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer’s disease.
The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer’s disease.
Authors: Vanmierlo, Tim | Bloks, Vincent W. | van Vark-van der Zee, Leonie C. | Rutten, Kris | Kerksiek, Anja | Friedrichs, Silvia | Sijbrands, Eric | Steinbusch, Harry W. | Kuipers, Folkert | Lütjohann, Dieter | Mulder, Monique
Article Type: Research Article
Abstract: Disturbances in cerebral cholesterol metabolism have been implicated in the pathogenesis of Alzheimer's disease (AD). Here, we provide evidence that alterations in brain cholesterol homeostasis also can be a consequence of disease progression. We found that APPSLxPS1mut mice, at the age of 9 months when AD-like pathology starts to develop, display increased levels of the cholesterol precursor desmosterol and of the cholesterol metabolite 27-hydroxy(OH)cholesterol in their cerebellum in comparison with wild-type controls. At the age of 21 months, when APPSLxPS1mut brain contains abundant amyloid deposits, desmosterol levels had further increased (> 200% in comparison with wild-type mice) in all brain …regions examined. 24(S)-OHcholesterol levels were increased in hippocampus and cerebellum of the APPSLxPS1mut mice, while 27-OHcholesterol levels were increased in cerebellum exclusively. Brain cholesterol levels remained unaffected. In line with the fact that desmosterol and 24(S)-OHcholesterol are Liver X Receptor (LXR) activators, the LXR-target genes Abca1 and Apoc1 were upregulated predominantly in hippocampus of APPSLxPS1mut mice at both ages evaluated. The reduced expression of the enzyme that converts desmosterol into cholesterol, the Selective AD indicator 1 gene (Seladin-1/Dhcr24), in both cortex and cerebellum may underlie the increased desmosterol levels in 21 month-old APPSLxPS1mut mice. Show more
Keywords: APPSLxPS1mut, Alzheimer's disease, brain cholesterol metabolism, LXR, oxysterols, seladin
DOI: 10.3233/JAD-2010-1209
Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 117-127, 2010
Authors: Erol, Adnan
Article Type: Research Article
Abstract: The progression and outcome of neurological diseases are determined by the balance between neurodegeneration, neuroprotection, and neuroregeneration. In this context, astroglial cells are invariably involved in every kind of neuropathology. Mitotically, active glial cells provide metabolic support to active neurons, contribute to coupling between synaptic activity and local blood flow, and thus protect against oxidative stress. Disturbances of the complex neuron-glia interrelation are increasingly recognized as a potentially important pathophysiological mechanism in a wide variety of neurological disorders including those marked by neurodegeneration. Peripheral insulin resistance-mediated increased oxidative stress in glial cells, and consequent DNA damage, induces senescence in glial …cells leads to the development of an inflammatory environment. The immune mediators released by senescent (activated) glial cells are considered to be neurotoxic and ultimately increase the oxidant load of neurons. While the neuron is viewed as the prototypical post-mitotic, fully differentiated cell, certain subsets of neurons reactivate cell-cycle activity in response to triggers of neuronal apoptosis, such as genotoxic stress generated by redox changes due to pathological alterations in supporting astroglial cells. Thus, a paradoxical cell cycle block in glial cells coupled with concomitant cell cycle re-entry in neurons (due to pathological alterations created by peripheral insulin resistance-induced neuroendocrine signaling changes) may cause neurodegeneration, such as seen in Alzheimer's disease. Show more
Keywords: Alzheimer's disease, cell cycle, glia, oxidative stress, p38, p53, senescence
DOI: 10.3233/JAD-2010-1211
Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 129-135, 2010
Authors: Nunes, Teresa | Fragata, Isabel | Ribeiro, Filipa | Palma, Teresa | Maroco, João | Cannas, Jorge | Secca, Mário | Menezes, Cristina | Carmo, Isabel | Cunha, Gil | Branco, Miguel Castelo | Guerreiro, Manuela | de Mendonça, Alexandre
Article Type: Research Article
Abstract: Elderly patients may present with prominent cognitive complaints and have performances in neuropsychological tests within the normal range for the age and education, and thus do not fulfill the criteria for mild cognitive impairment (MCI). There is insufficient evidence to support the clinical decision in these cases (“pre-MCI”). Forty-three subjects, 11 controls, 15 “pre-MCI,” and 17 MCI, were followed for about three and half years with neuropsychological testing and magnetic resonance imaging including volumetric measurements of the hippocampus and amygdala. Two of the “pre-MCI” subjects suffered cognitive and functional deterioration and were diagnosed with dementia. Although the “pre-MCI” subjects as …a group had no significant deterioration in neuropsychological tests, they suffered a decline in the total hippocampal volume (P=0.04) along the follow-up time. In contrast, all control subjects remained stable and had no volumetric decreases. As expected, MCI patients underwent significant deterioration in several neuropsychological tests, often progressed to Alzheimer's disease, and showed decreases both in total hippocampal and amygdalar volumes. Elderly people presenting with cognitive complaints may be in an initial phase of a degenerative disorder and should be followed clinically, even if they have normal neuropsychological tests. Show more
Keywords: Aging, Alzheimer's disease, amygdala, dementia, hippocampus, magnetic resonance imaging, mild cognitive impairment (MCI), pre-MCI, volumetry
DOI: 10.3233/JAD-2010-1210
Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 137-145, 2010
Authors: Serra, Laura | Cercignani, Mara | Lenzi, Delia | Perri, Roberta | Fadda, Lucia | Caltagirone, Carlo | Macaluso, Emiliano | Bozzali, Marco
Article Type: Research Article
Abstract: This study investigates abnormalities of grey (GM) and white matter (WM) in Alzheimer's disease (AD), by modeling the AD pathological process as a continuous course between normal aging and fully developed dementia, with amnesic mild cognitive impairment (aMCI) as an intermediate stage. All subjects (9 AD, 16 aMCI patients, and 13 healthy controls) underwent a full neuropsychological assessment and an MRI examination at 3 Tesla, including a volumetric scan and diffusion tensor (DT)-MRI. The volumes were processed to perform a voxel-based morphometric analysis of GM and WM volume, while DT-MRI data were analyzed using tract based spatial statistics, to estimate …changes in fractional anisotropy and mean diffusivity data. GM and WM volume and mean diffusivity and fractional anisotropy were compared across the three groups, and their correlation with cognitive functions was investigated. While AD presented a pattern of widespread GM atrophy, tissue loss was more subtle in patients with aMCI. WM atrophy was mainly located in the temporal lobe, but evidence of WM microscopic damage, assessed by DT-MRI, was also observable in the thalamic radiations and in the corpus callosum. Memory and executive functions correlated with either GM volume or fractional anisotropy in fronto-temporal areas. In conclusion, this study shows a comprehensive assessment of the brain tissue damage across AD evolution, providing insights on different pathophysiological mechanisms (GM atrophy, Wallerian degeneration, and brain disconnection) and their possible association with clinical aspects of cognitive decline. Show more
Keywords: Alzheimer's disease, diffusion tensor MRI, mild cognitive impairment, neuropsychology, tract-based spatial statistics, voxel based morphometry
DOI: 10.3233/JAD-2010-1223
Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 147-159, 2010
Authors: Li, Mi | Sun, Miao | Liu, Yi | Yu, Jia | Yang, Huan | Fan, Dongsheng | Chui, Dehua
Article Type: Research Article
Abstract: Copper plays a central role in conserved processes such as respiration, and in highly specialized processes, such as protein modification. The metalloprotease neprilysin (NEP) degrades a variety of bioactive peptides and is involved in many physiological processes. However, very little is known about the regulation of NEP activity. In the current study, we focused on the effect of Cu2+ on the enzymatic activity and protein stability of NEP. Using mouse neuroblastoma N2a cells, we found that the enzymatic activity of NEP was decreased by treatment with Cu2+ in a dose- and time-dependent manner. In our investigation of the …mechanism by which Cu2+ downregulates NEP enzyme activity, we found that treatment with Cu2+ caused a decrease in the level of NEP as determined by Western blot analysis. Quantitative analysis of NEP mRNA with RT-PCR excluded the possibility that Cu2+ downregulates NEP protein at the gene transcription level. Moreover, specific proteasome inhibitors, MG132 and lactacystin, blocked the turnover of NEP, whereas inhibitors of lysosome had no significant effect, suggesting that Cu2+ -induced degradation of NEP is via a proteasome pathway. Taken together, our data suggest that copper downregulates NEP activity through modulation of NEP protein degradation. Show more
Keywords: Activity, copper, degradation, neprilysin
DOI: 10.3233/JAD-2010-1218
Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 161-169, 2010
Authors: Galimberti, Daniela | Fenoglio, Chiara | Cortini, Francesca | Serpente, Maria | Venturelli, Eliana | Villa, Chiara | Clerici, Francesca | Marcone, Alessandra | Benussi, Luisa | Ghidoni, Roberta | Gallone, Salvatore | Scalabrini, Diego | Restelli, Ilaria | Boneschi, Filippo Martinelli | Cappa, Stefano | Binetti, Giuliano | Mariani, Claudio | Rainero, Innocenzo | Giordana, Maria Teresa | Bresolin, Nereo | Scarpini, Elio
Article Type: Research Article
Abstract: Mutations in the progranulin gene (GRN) are responsible for familial FTLD with ubiquitin pathology (FTLD-U). However, there are controversial data regarding the contribution of GRN variability to sporadic FTLD. We carried out an association study in 265 patients, who did not carry a GRN causal mutation, and 375 age-matched controls. Four tagging Single Nucleotide Polymorphisms (SNPs) were chosen generate 80% power to detect an allelic association with P ⩽ 0.01. In addition, a known functional SNP (rs5848) was included. An increased frequency of the rs4792938 CC genotype in cases compared with controls was observed (17.4 versus 10.4%, P=0.01, OR: 1.81, …95%CI: 1.15–2.85). Stratifying for gender, no differences were observed for all polymorphisms. Haplotype analysis failed to detect haplotypes associated with the disease. Our findings indicate that the GRN rs4792938 CC genotype represents a susceptibility factor for the development of FTLD in individuals who do not carry GRN causal mutations. This SNP is likely located in a regulatory region, thus an effect on GRN mRNA levels may be of mechanistic importance. Show more
Keywords: Frontotemporal Lobar Degeneration (FTLD), polymorphism, progranulin (GRN), risk factor, variability
DOI: 10.3233/JAD-2010-1225
Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 171-177, 2010
Authors: Wang, Rui | Malter, James S. | Wang, Deng-Shun
Article Type: Research Article
Abstract: As one of the dominant amyloid-β peptide (Aβ) proteases, neprilysin (NEP) plays a crucial role in maintaining a physiologic balance between Aβ production and catabolism. We have previously shown that NEP is modified by 4-hydroxynonenal (HNE) adducts, resulting in decreased activity in the brain of AD patients and cultured cells. In order to determine whether antioxidants can rescue NEP, SH-SY5Y cells were treated with HNE or Aβ, together with N-acetylcysteine for 24 hours, prior to analysis of NEP protein levels, activity, and oxidative modifications. Intracellular NEP developed HNE adducts after 24 hours of HNE or Aβ treatment as determined by …immunoprecipitation, immunoblotting, and double immunofluorescence staining. N-acetylcysteine at 10 to 100 μM alleviated HNE adduction after HNE or Aβ treatment. In keeping with previous reports, HNE-modified NEP showed decreased catalytic activity. The present study demonstrates that antioxidants can be used to spare NEP from oxidative modification, suggesting a potential mechanism underlying the neuroprotective effects of antioxidants in aging or Alzheimer's disease. Show more
Keywords: Alzheimer's disease, amyloid-β, antioxidant, degradation, 4-hydroxynonenal, N-acetylcysteine, neprilysin, oxidative stress
DOI: 10.3233/JAD-2010-1226
Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 179-189, 2010
Authors: Arendash, Gary W. | Sanchez-Ramos, Juan | Mori, Takashi | Mamcarz, Malgorzata | Lin, Xiaoyang | Runfeldt, Melissa | Wang, Li | Zhang, Guixin | Sava, Vasyl | Tan, Jun | Cao, Chuanhai
Article Type: Research Article
Abstract: Despite numerous studies, there is no definitive evidence that high-frequency electromagnetic field (EMF) exposure is a risk to human health. To the contrary, this report presents the first evidence that long-term EMF exposure directly associated with cell phone use (918 MHz; 0.25 w/kg) provides cognitive benefits. Both cognitive-protective and cognitive-enhancing effects of EMF exposure were discovered for both normal mice and transgenic mice destined to develop Alzheimer's-like cognitive impairment. The cognitive interference task utilized in this study was designed from, and measure-for-measure analogous to, a human cognitive interference task. In Alzheimer's disease mice, long-term EMF exposure reduced brain amyloid-β (Aβ) …deposition through Aβ anti-aggregation actions and increased brain temperature during exposure periods. Several inter-related mechanisms of EMF action are proposed, including increased Aβ clearance from the brains of Alzheimer's disease mice, increased neuronal activity, and increased cerebral blood flow. Although caution should be taken in extrapolating these mouse studies to humans, we conclude that EMF exposure may represent a non-invasive, non-pharmacologic therapeutic against Alzheimer's disease and an effective memory-enhancing approach in general. Show more
Keywords: Alzheimer's disease, amyloid-β, electromagnetic fields, memory, transgenic mice
DOI: 10.3233/JAD-2010-1228
Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 191-210, 2010
Authors: Landhuis, Esther | Dance, Amber
Article Type: Research Article
DOI: 10.3233/JAD-2010-1256
Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 211-216, 2010
Authors: Lovell, Mark A.
Article Type: Editorial
DOI: 10.3233/JAD-2010-1263
Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 219-219, 2010
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