Journal of Alzheimer's Disease - Volume 30, issue 3

Authors: Klugman, Anthony | Naughton, Declan P. | Isaac, Mokhtar | Shah, Iltaf | Petroczi, Andrea | Tabet, Naji

Article Type: Research Article

Abstract: The mode of action of acetylcholinesterase inhibitors (AChEIs) in Alzheimer's disease (AD) is mainly by potentiating neuronal transmission. Animal studies have also consistently described a role for AChEIs in enhancement of antioxidants and attenuation of oxidative stress. The influence of AChEIs on blood antioxidants in AD patients has not been established before. Furthermore, AChEI treatment, or lack of it, may have contributed to the inconsistent antioxidant data reported by other studies so far. Here we sought to investigate the potential modulation effect of AChEIs on blood antioxidants in AD patients. Catalase (CAT) and glutathione reductase (GR) activities were analyzed in …25 drug naïve patients (Group A), 43 patients receiving AChEIs (Group B) and 34 cognitively unimpaired controls (Group C). A statistically significant difference for CAT and GR was observed between the two AD groups (A and B) when compared to the control group C (KW-H = 36.530, p < 0.001; post hoc tests p < 0.001 and KW-H = 37.814, p < 0.001; post hoc tests p < 0.001, respectively). In contrast, CAT and GR activities did not differ significantly between the two AD groups, and were not influenced by AChEI treatment. Hence, these results do not replicate the extensively reported data from animal studies and question whether AChEI efficacy in AD is mediated by processes beyond neuron to neuron enhancement of transmission. Studies assessing a wider range of oxidative/inflammatory markers taking into account type, dosage, and treatment duration of the various acetylcholinesterase inhibitors are now needed. Show more

Keywords: Acetylcholinesterase inhibitors, Alzheimer's disease, antioxidants, catalase, glutathione reductase, oxidative stress

DOI: 10.3233/JAD-2012-120124

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 467-474, 2012

Authors: Liang, Peipeng | Wang, Zhiqun | Yang, Yanhui | Li, Kuncheng

Article Type: Research Article

Abstract: The Inferior parietal cortex (IPC), including the intraparietal sulcus (IPS), angular gyrus (AG), and supramarginal gyrus (SG), plays an important role in episodic memory, and is considered to be one of the specific neuroimaging markers in predicting the conversion of mild cognitive impairment (MCI) to Alzheimer's disease (AD). However, it is still unclear whether the connectivity of the IPC is impaired in MCI patients. In the present study, we used resting state fMRI to examine the functional connectivity of the three subdivisions of the IPC in MCI patients after controlling the impact of regional grey matter atrophy. It was found …that, using IPS, AG, and SG as seeds of functional connectivity, three canonical functional networks could be correspondingly traced, i.e., executive control network (ECN), default mode network (DMN), and salience network (SN), and the three networks are differently altered in MCI patients. In contrast to the healthy controls, it was found that in MCI patients: 1) AG connectivity was significantly reduced within the DMN; 2) IPS showed decreased connectivity with the right inferior frontal gyrus while showing increased connectivity with the left frontal regions within the ECN; and 3) SG displayed decreased connectivity with a distribution of regions including the frontal and parietal regions, and increased connectivity with some sub-cortical areas within the SN. Moreover, the connectivity within the three networks was correlated with episodic memory and general cognitive impairment in MCI patients. These results extend well beyond the DMN, and further suggest that MCI is associated with alteration of large-scale functional brain networks. Show more

Keywords: Functional connectivity, functional magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-2012-111721

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 475-487, 2012

Authors: Saint-Pol, Julien | Vandenhaute, Elodie | Boucau, Marie-Christine | Candela, Pietra | Dehouck, Lucie | Cecchelli, Roméo | Dehouck, Marie-Pierre | Fenart, Laurence | Gosselet, Fabien

Article Type: Research Article

Abstract: In brain, excess cholesterol is metabolized into 24S-hydroxycholesterol (24S-OH-chol) and eliminated into the circulation across the blood-brain barrier. 24S-OH-chol is a natural agonist of the nuclear liver X receptors (LXRs) involved in peripheral cholesterol homeostasis. The effects of this oxysterol on the pericytes embedded in the basal lamina of this barrier (close to the brain compartment) have not been previously studied. We used primary cultures of brain pericytes to demonstrate that the latter express LXR nuclear receptors and their target gene ATP-binding cassette, sub-family A, member 1 (ABCA1), known to be one of the major transporters involved in peripheral lipid …homeostasis. Treatment with 24S-OH-chol caused an increase in ABCA1 expression that correlated with a reverse cholesterol transfer to apolipoprotein E, apolipoprotein A-I, and high density lipoprotein particles. Inhibition of ABCA1 decreased this efflux. As pericytes are able to internalize the amyloid-β peptides which accumulate in brain of Alzheimer's disease patients, we then investigated the effects of 24S-OH-chol on this process. We found that the cellular accumulation process was not modified by 24S-OH-chol treatment. Overall, our results highlight the importance of the LXR/ABCA1 system in brain pericytes and suggest a new role for these cells in brain cholesterol homeostasis. Show more

Keywords: 24S-hydroxycholesterol, ABCA1, Alzheimer's disease, amyloid-β peptides, liver X receptors, pericytes

DOI: 10.3233/JAD-2012-112090

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 489-503, 2012

Authors: Diaz, Alfonso | Limon, Daniel | Chávez, Raúl | Zenteno, Edgar | Guevara, Jorge

Article Type: Research Article

Abstract: Amyloid-β (Aβ)25-35 is able to cause memory impairment and neurodegenerative events. Recent evidence has shown that the injection of Aβ25-35 into the temporal cortex (TCx) of rats increases the inflammatory response; however, it is unclear how the inflammatory process could be involved in the progression of Aβ25-35 toxicity. In this study we investigated the role of inflammation in the neuronal damage and spatial memory impairment generated by Aβ25-35 in rat TCx using immunohistochemistry, ELISA, and a behavioral test in the radial maze. Our findings show that Aβ25-35 -injection into the TCx induced a reactive gliosis …(GFAP and CD11b-reactivity) and an increase of pro-inflammatory cytokines (IL-1β, IL-6, IL-17, and TNF-α) in the TCx and the hippocampus at 5, 15, and 30 days after injection. Thirty days after Aβ25-35 injection, we observed that the inflammatory reaction probably contributed to increase the immunoreactivity of inducible nitric oxide synthase and nitrite levels, as well as to the loss of neurons in TCx and hippocampus. Behavioral performance showed that the neurodegeneration evoked by Aβ25-35 delayed acquisition of learning and impaired spatial memory, because the Aβ25-35 -treated animals showed a greater number of errors during the task than the control group. Previous administration of an interleukin receptor antagonist (IL-1ra) (10 and 20 μg/μL, into TCx), an anti-inflammatory agent, suppressed the Aβ25-35 -induced inflammatory response and neurodegeneration, as well as memory dysfunction. This study suggests that the chronic inflammatory reaction could contribute to the progression of Aβ25-35 toxicity and cause cognitive impairment. Show more

Keywords: Alzheimer's disease, astrocytes, cytokines, iNOS, memory, microglia, neurodegeneration

DOI: 10.3233/JAD-2012-111979

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 505-522, 2012

Authors: Wan, Li | Nie, Guangjun | Zhang, Jie | Zhao, Baolu

Article Type: Research Article

Abstract: The accumulation of amyloid-β protein precursor (AβPP) is related to the pathogenesis of Alzheimer's disease (AD); however, the underlying mechanism is still unclear. The abnormal interactions of AβPP with metal ions such as iron are implicated in the process of oxidative stress in AD brains. In this study, we found that the overexpression of wild-type human AβPP695 decreased the iron content and increased the oxidative stress in neuroblastoma SH-SY5Y cells. The catalase activity of stably transfected cells overexpressing wild-type AβPP695 (AβPP cells) was significantly lower than that of the control cells. Intracellular reactive oxygen species (ROS) generation and calcium levels …significantly increased in AβPP cells compared to control cells. The mitochondrial membrane potential of AβPP cells was significantly lower than that of the control cells. Moreover, iron treatment decreased ROS and calcium levels and increased cell viability of AβPP cells. The iron deficiency in AβPP cells may contribute to the pathogenesis of AD. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, iron deficiency, oxidative stress

DOI: 10.3233/JAD-2012-111169

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 523-530, 2012

Authors: Wei, LiFei | Yang, Hui | Xie, ZhaoHong | Yang, ShaoNan | Yang, HongNa | Zhao, CuiPing | Wang, Ping | Xu, ShunLiang | Miao, JunYing | Zhao, BaoXiang | Bi, JianZhong

Article Type: Research Article

Abstract: Excessive extracellular deposition of amyloid- peptide (Aβ) in the brain is the pathological hallmark of Alzheimer's disease (AD). Cumulative evidence indicates that autophagy is involved in the metabolism of Aβ and pathogenesis of AD. However, the molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. We recently found that long-term treatment with a butyrolactone derivative 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran- 2(3 H)-one (3BDO) increased levels of insulin-degrading enzyme and neprilysin, suppressed autophagy via an mTOR pathway, lowered levels of Aβ, and prevented AD-like cognitive deficits in the AβPP/PS1 double transgenic mouse …model. Therefore, our findings suggest that 3BDO may be beneficial in the prevention and treatment of AD. Show more

Keywords: AβPP/PS1 mouse, Alzheimer's disease, amyloid-β peptides, autophagy, insulin-degrading enzyme, neprilysin

DOI: 10.3233/JAD-2012-111985

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 531-543, 2012

Authors: Long, Jiangang | He, Ping | Shen, Yong | Li, Rena

Article Type: Research Article

Abstract: Accumulating evidence suggests that mitochondria are important targets for the actions of estrogens and studies indicated that localization of estrogen receptor β (ERβ) in neuronal mitochondrial (mtERβ) might directly affect neuronal mitochondrial function in vitro. However, it is unknown what expression levels and how important mtERβ is in the human brain, particularly in a brain with Alzheimer's disease (AD). In the present study, using rapidly autopsied human brain tissue, we found that the frontal cortices of female AD patients exhibited significantly reduced mtERβ, along with reduced mitochondrial cytochrome C oxidase activity, and increased protein carbonylation compared to that in normal …controls. The correlation between mtERβ expression and mitochondrial cytochrome C oxidase activity in the female human brain is significant. To understand the possible mechanisms of mtERβ in AD-related mitochondrial dysfunction, using ERβKO mice as a model, we found that lack of ERβ enhanced brain reactive oxygen species generation and reduced mitochondrial membrane potential under Aβ peptide insult compared to brain mitochondria from wild-type control mice. Our studies, for the first time, demonstrated neuronal mtERβ expression in the human brain and the deficiency of mtERβ in the female AD brain is associated with the dysfunction of mitochondria. Our results from ERβKO mice demonstrated that ERβ depletion-induced mitochondrial dysfunction is mediated through increasing reactive oxygen generation and reduction of mitochondria membrane potential. These results indicate that ERβ depletion impairs mitochondrial function in mice, and reduction of brain mtERβ may significantly contribute to the mitochondrial dysfunction involved in AD pathogenesis in women. Show more

Keywords: Alzheimer's disease, brain mitochondria estrogen receptor β (mtERβ), mitochondria dysfunction

DOI: 10.3233/JAD-2012-120283

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 545-558, 2012

Authors: Cao, Chuanhai | Loewenstein, David A. | Lin, Xiaoyang | Zhang, Chi | Wang, Li | Duara, Ranjan | Wu, Yougui | Giannini, Alessandra | Bai, Ge | Cai, Jianfeng | Greig, Maria | Schofield, Elizabeth | Ashok, Raj | Small, Brent | Potter, Huntington | Arendash, Gary W.

Article Type: Research Article

Abstract: Although both human epidemiologic and animal model studies have suggested that caffeine/coffee protects against Alzheimer's disease, direct human evidence for this premise has been lacking. In the present case-control study, two separate cohorts consisting of 124 total individuals (65–88 years old) were cognitively assessed and a blood sample taken for caffeine/biomarker analysis. Subjects were then monitored for cognitive status over the ensuing 2–4 year period to determine the extent to which initial plasma caffeine/biomarkers levels would be predictive of changes in cognitive status. Plasma caffeine levels at study onset were substantially lower (−51%) in mild cognitive impairment (MCI) subjects who …later progressed to dementia (MCI→DEM) compared to levels in stable MCI subjects (MCI→MCI). Moreover, none of the MCI→DEM subjects had initial blood caffeine levels that were above a critical level of 1200 ng/ml, while half of stable MCI→MCI subjects had blood caffeine levels higher than that critical level. Thus, plasma caffeine levels greater than 1200 ng/ml (≈6 μM) in MCI subjects were associated with no conversion to dementia during the ensuing 2–4 year follow-up period. Among the 11 cytokines measured in plasma, three of them (GCSF, IL-10, and IL-6) were decreased in MCI→DEM subjects, but not in stable MCI→MCI subjects with high plasma caffeine levels. Coffee would appear to be the major or perhaps only source of caffeine for such stable MCI patients. This case-control study provides the first direct evidence that caffeine/coffee intake is associated with a reduced risk of dementia or delayed onset, particularly for those who already have MCI. Show more

Keywords: Alzheimer's disease, caffeine, coffee, dementia, immune response, mild cognitive impairment, plasma cytokines

DOI: 10.3233/JAD-2012-111781

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 559-572, 2012

Authors: Casadesús, Gemma | Gutierrez-Cuesta, Javier | Lee, Hyoung-gon | Jiménez, Andrés | Tajes, Marta | Ortuño-Sahagún, Daniel | Camins, Antoni | Smith, Mark A. | Pallàs, Mercè

Article Type: Research Article

Abstract: Senescence-accelerated mice 8 (SAMP8), a model of aging, display many established pathological features of Alzheimer's disease (AD); however, whether cell cycle alterations exist in these animals remains unknown. Given that these animals present changes such as tau phosphorylation and redox imbalance, both associated with cell cycle alterations, we determined whether changes in cell cycle markers were present in SAMP8 and SAMR1 (control strain) at 3, 6, and 9 months-old brains. As expected, an increase in tau hyperphosphorylation and its associated machinery, i.e., cdk5 and GSK3β, was observed both between strains and also with aging. Particularly, significant differences in cyclin A, …cyclin D1, cyclin E, Cdk2, cyclin B, pR, and E2F1 were found when comparing SAMP8 to SAMR1. More interestingly, a partial correlation with several cell cycle markers described in AD brain is found in SAMP8, indicating that some specific hallmarks of AD are also present in this strain, which has been postulated as an early switch model of the disease. Show more

Keywords: Aging, Alzheimer's disease, cdk5, cell cycle, GSK3β, tau

DOI: 10.3233/JAD-2012-120112

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 573-583, 2012

Authors: Chen, Ning-Ning | Luo, Dan-Ju | Yao, Xiu-Qing | Yu, Cong | Wang, Yi | Wang, Qun | Wang, Jian-Zhi | Liu, Gong-Ping

Article Type: Research Article

Abstract: Pesticides are widely used in agriculture, and epidemiological studies suggest that pesticide exposure is a risk factor for Alzheimer's disease (AD), but the mechanisms are elusive. Here, we studied the effects of pesticide exposure on the cognitive ability and the underlying mechanisms in rats. Deltamethrin and carbofuran were administered respectively into the rats once a day for 28 days by gavage. We found that pesticide exposure induced spatial learning and memory deficits with a simultaneous decrease of N-methyl-D-aspartate receptor 1, synaptophysin, and synapsin I, all of which are memory-related synaptic proteins. Pesticide exposure also induced tau hyperphosphorylation at multiple AD-related …phosphorylation sites with activation of glycogen synthase kinase-3β and inhibition of protein phosphatase-2A. Additionally, neuron loss in the hippocampus and cortex was observed upon administration of the pesticides. These results indicate that the pesticides exposure could induce AD-like pathology and cognitive abnormality in rats. Show more

Keywords: Alzheimer's disease, glycogen synthase kinase-3β, pesticides, protein phosphatase-2A, tau

DOI: 10.3233/JAD-2012-111946

Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 585-594, 2012