Journal of Alzheimer's Disease - Volume 64, issue 3

Authors: Li, Bingyu | Xu, Pengli | Wu, Shuyan | Jiang, Zhixian | Huang, Zhijian | Li, Qian | Chen, Danhong

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a neurodegenerative disease characterized by loss of dopaminergic neurons in the substantia nigra. Diosgenin is a natural steroid saponin which was shown to play a beneficial role in Alzheimer’s disease. Objective: This study sought to investigate the potential effect of diosgenin on a rat model of PD. Methods: Sprague Dawley rats were subjected to intra-striatal injection of lipopolysaccharide (LPS) and treated with diosgenin. Stepping, Whisker, and Cylinder tests were carried out to determine the motor function, and the expression of tyrosine hydroxylase was detected by immunohistochemistry. The levels of multiple proinflammatory …cytokines, oxidative stress related factors and proteins involved in Toll-like receptor (TLR)/nuclear factor kappa B (NF-κ B) pathway were measured. The synergistic effect of environment enrichment on diosgenin was also investigated. Results: Intra-striatal injection of LPS caused motor deficits in rats, induced inflammatory response and oxidative stress response, and activated the TLR/NF-κ B pathway both in vivo and in vitro . Diosgenin could attenuate the LPS-induced alterations. Enriched environment enhanced the effect of diosgenin to ameliorate the LPS-induced motor deficits in rats and decreased the protein levels of TLR2, TLR4, and nuclear NF-κ B in diosgenin treated PD rats. Conclusion: Diosgenin had a beneficial effect in LPS-induced rat PD models, by suppressing the TLR/NF-κ B signaling pathway. Environmental enrichment could play a synergistic effect with diosgenin, by enhancing the inhibitory effect of diosgenin on the TLR/ NF-κ B signaling pathway. Show more

Keywords: Diosgenin, environment enrichment, lipopolysaccharide, Parkinson’s disease, Toll-like receptor/nuclear factor kappa B pathway

DOI: 10.3233/JAD-180330

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 943-955, 2018

Authors: Wang, Lin | Shi, Fang-Xiao | Xu, Wei-Qi | Cao, Yun | Li, Na | Li, Man | Wang, Qun | Wang, Jian-Zhi | Tian, Qing | Yu, Li-Kai | Zhou, Xin-Wen

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by neuritic plaques and neurofibrillary tangles. It is reported that enzymatic degradation of amyloid-β (Aβ) plays a pivotal role in Aβ accumulation and type-2 cannabinoid receptor (CB2R) participates in Aβ processing in the brain; however, the underlying mechanisms remain unclear. We determined that Aβ degradation-related proteins are significantly different between CB2R–/– mice and wild-type (WT) mice via proteomic analysis. Moreover, the data demonstrated that the angiotensin converting enzyme (ACE) and insulin-degrading enzyme (IDE) levels are substantially attenuated, and the Aβ level is significantly enhanced in CB2R–/– -Aβ1 - 42 mice compared with that of WT-Aβ1 - 42 …mice. Furthermore, Aβ-mediated synaptic dysfunction, the loss of memory associated proteins, and the suppression of glutamatergic transmission are more severe in CB2R–/– -Aβ1 - 42 mice than that in WT-Aβ1 - 42 mice. CB2R activation could decrease Aβ1 - 40 and Aβ1 - 42 levels and enhance ACE and IDE levels with its selective agonist JWH133; however, AM630 (CB2R antagonist) abrogates all changes induced by JWH133 in N2a cells with AβPP overexpression. Taken together, our study demonstrated that the deletion of CB2R reduces exogenous Aβ degradation and aggravates the toxicity of Aβ via the reduction of ACE and IDE, which suggests that CB2R is involved in the onset of AD and a potential therapeutic target for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β degradation, angiotensin converting enzyme, type 2-cannabinoid receptors, insulin-degrading enzyme

DOI: 10.3233/JAD-180142

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 957-971, 2018

Authors: Pillai, Jagan A. | Appleby, Brian S. | Safar, Jiri | Leverenz, James B.

Article Type: Research Article

Abstract: Background: A rapidly progressive phenotype of Alzheimer’s disease (AD) has been described in some prion disease cohorts. Limited information regarding rapidly progressive AD (rpAD) is available from longitudinal national cohorts. Objective: To compare the clinical characteristics of rpAD in two different national cohorts. Methods: A retrospective analysis was performed on AD subjects with available neuropathology in the National Alzheimer’s Coordinating Center (NACC) database and among neuropathologically characterized AD cases from the National Prion Disease Pathology Surveillance Center (NPDPSC) that were evaluated for suspected prion disease. In the NACC cohort, rpAD was delineated by the lower 10th …percentile of follow up duration from pre-dementia to death duration among subjects meeting pathological diagnosis of AD. Results: rpAD from the NPDPSC had a shorter mean symptom duration than the NACC identified rpAD cases (11.6 months versus 62.4 months) and were also younger at the time of their death (60.0 versus 81.8 years). NACC identified rpAD subjects, beginning from a predementia stage, had slower rate of MMSE change per year than NPDPSC cases (2.5 versus 6.0 points). Conclusions: rpAD constitute an important subset of AD subjects in whom a rapid course of symptomatic clinical decline is noted, as confirmed in both national cohorts. rpAD was best characterized by survival time (≤3 years), as there were clear differences between the rpAD cohorts in terms of symptom duration, age at death, and MMSE change per year, likely due to the strong selection biases. rpAD could shed light on the biology of rate of progression in AD. Show more

Keywords: Alzheimer’s disease, dementia, rapidly progressive dementia, rate of decline

DOI: 10.3233/JAD-180155

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 973-980, 2018

Authors: Femminella, Grazia Daniela | Taylor-Davies, Genevieve | Scott, James | Edison, Paul | the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Cardiovascular risk could be calculated using Qrisk2. It is suggested that cardiovascular risk factors influence the progression of Alzheimer’s disease (AD). However, studies have not specifically evaluated the influence of cardiovascular risk using Qrisk2 on neuropathological progression and AD biomarkers. The aim of the study was to evaluate the influence of cardiovascular risk factors using Qrisk2 on CSF amyloid-β (Aβ) and tau, 18 F-AV45-PET, 18 F-FDG-PET, MRI, and cognitive measures in APOE4 negative cognitively normal and mild cognitive impairment (MCI) subjects. 614 cognitively normal, early, and late MCI subjects were selected from the ADNI cohort with a 2-year follow-up. CSF …Aβ and tau, 18 F-AV45-PET, 18 F-FDG-PET, MRI, and cognitive measures along with modified Qrisk2 were evaluated. APOE4 non-carrier, high cardiovascular risk sub-group of early and late MCI and cognitively normal subjects, demonstrated worse biomarker and cognitive profile at baseline and during follow up compared to low cardiovascular risk group. Additionally, similar pattern was also observed in APOE4 carriers. We demonstrated that Qrisk2 and APOE4 were independent predictors of biomarker and clinical progression in AD trajectory. High cardiovascular risk is associated with biomarker changes in APOE4 non-carriers in prodromal AD, which may suggest that treatment of cardiovascular risk is an effective prevention strategy even in APOE4 negative subjects and may influence disease progression independent of amyloid pathology. Demonstration of accelerated neuropathological changes in both APOE4 carriers and non-carriers suggest that focusing on modifiable cardiovascular risk factors is an effective preventative strategy while we eagerly waiting for new treatments. Show more

Keywords: Alzheimer’s disease, APOE4, biomarkers, cardiovascular disease, risk factors

DOI: 10.3233/JAD-180365

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 981-993, 2018

Authors: Derk, Julia | Bermudez Hernandez, Keria | Rodriguez, Moises | He, Meilun | Koh, Hyunwook | Abedini, Andisheh | Li, Huilin | Fenyö, David | Schmidt, Ann Marie

Article Type: Research Article

Abstract: Background: The receptor for advanced glycation end products (RAGE) is linked to cellular stress and inflammation during Alzheimer’s disease (AD). RAGE signals through Diaphanous-1 (DIAPH1); however, the expression of DIAPH1 in the healthy and AD human brain has yet to be methodically addressed. Objective: To delineate the cell- and disease-state specific expression of DIAPH1 in the human medial temporal cortex during healthy aging and AD. Methods: We used semi-quantitative immunohistochemistry in the human medial temporal cortex paired with widefield and confocal microscopy and automated analyses to determine colocalization and relative …expression of DIAPH1 with key cell markers and molecules in the brains of subjects with AD versus age-matched controls. Results: We report robust colocalization of DIAPH1 with myeloid cells and increased expression during AD, which strongly correlated to increased neutral lipids and morphology of inflamed myeloid cells. DIAPH1 moderately colocalized with markers of endothelial cells, astrocytes, neurons, and oligodendrocytes. Discussion: Our findings localize DIAPH1 particularly to myeloid cells in the CNS, especially in AD in the locations of lipid droplet accumulation, thereby implicating RAGE-DIAPH1 signaling in dysregulated lipid metabolism and morphological changes of inflamed myeloid cells in this disorder. Show more

Keywords: Alzheimer’s disease, DIAPH1, myeloid cells, microglia, lipids, inflammation, RAGE

DOI: 10.3233/JAD-180088

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 995-1007, 2018

Authors: Dias, Irundika H.K. | Brown, Caroline L. | Shabir, Kiran | Polidori, M. Cristina | Griffiths, Helen R.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) etiology is complex; gene and environmental risk factors may interact to predispose to disease. From single nucleotide polymorphism analyses and genome-wide association studies, a number of candidate risk genes for the onset of AD have been identified and cluster around lipid metabolism and inflammation. We hypothesized that endothelial cells which line the blood-brain barrier are likely to be critical mediators of systemic metabolism within the brain. Therefore, we have studied the effect of 27 hydroxycholesterol (27-OHC) on microvascular endothelial cell (HMVEC) redox state, inflammatory cytokine secretion, and microRNA (miR) expression. Using a transwell method, we have studied …directional secretion profiles for the proinflammatory cytokines TNFα and IL-6 and confirmed that 27-OHC induces discrete and directional inflammatory molecular signatures from HMVEC. The lipids caused depletion of cellular glutathione and cytokine secretion is HMVEC-redox state-dependent. Discovery miR expression change in HMVEC with and without 27-OHC treatment was undertaken. We selected three genes for further analysis by qPCR; miR-144 and 146 expression, which are anti-inflammatory and redox regulating modulators, were not affected significantly by 27-OHC. However, increased expression of a putative neurotrophic regulatory factor miR933 in HMVEC with 27-OHC was confirmed by qPCR. In plasma from patients with dementia, all three miR were found at significantly elevated levels compared to healthy older adults. These data highlight that 27-OHC has an important regulatory effect on endothelial microvascular cells to increase expression of a miR (–933) and secretion of inflammatory cytokines that are elevated in plasma from dementia patients. Show more

Keywords: Alzheimer’s disease, dementia, glutathione, inflammation, miRNA, neurotrophic factor, oxysterol, redox, vascular

DOI: 10.3233/JAD-180201

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 1009-1017, 2018

Article Type: Abstract

DOI: 10.3233/JAD-189006

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 1019-1048, 2018