Journal of Alzheimer's Disease - Volume 60, issue 3

Authors: Talan, Jamie

Article Type: Obituary

DOI: 10.3233/JAD-170820

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 747-749, 2017

Article Type: Other

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 751-751, 2017

Authors: Dinkins, Michael B. | Wang, Guanghu | Bieberich, Erhard

Article Type: Review Article

Abstract: Extracellular vesicles (EVs), particularly exosomes, have emerged in the last 10 years as a new player in the progression of Alzheimer’s disease (AD) with high potential for being useful as a diagnostic and treatment tool. Exosomes and other EVs are enriched with the sphingolipid ceramide as well as other more complex glycosphingolipids such as gangliosides. At least a subpopulation of exosomes requires neutral sphingomyelinase activity for their biogenesis and secretion. As ceramide is often elevated in AD, exosome secretion may be affected as well. Here, we review the available data showing that exosomes regulate the aggregation and clearance of amyloid-beta …(Aβ) and discuss the differences in data from laboratories regarding Aβ binding, induction of aggregation, and glial clearance. We also summarize available data on the role of exosomes in extracellular tau propagation, AD-related exosomal mRNA/miRNA cargo, and the use of exosomes as biomarker and gene therapy vehicles for diagnosis and potential treatment. Show more

Keywords: Alzheimer’s disease, amyloid, biomarker, ceramide, exosome, miRNA, sphingomyelinase, tau, vesicle

DOI: 10.3233/JAD-160567

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 757-768, 2017

Authors: den Hoedt, Sandra | Janssen, Carola I.F. | Astarita, Giuseppe | Piomelli, Daniele | Leijten, Frank P.J. | Crivelli, Simone M. | Verhoeven, Adrie J.M. | de Vries, Helga E. | Walter, Jochen | Martinez-Martinez, Pilar | Sijbrands, Eric J.G. | Kiliaan, Amanda J. | Mulder, Monique T.

Article Type: Research Article

Abstract: Background: Apolipoprotein E (ApoE) is known for its role in lipid trafficking and the ɛ 4 allele is a risk factor for late onset Alzheimer’s disease (AD). Recently, aberrant ceramide and fatty acid (FA) levels have been implicated in AD. Objective: To determine the specific effects of human ApoE4 (hE4) on cerebral ceramide and FA content during chow or a high fat/high cholesterol (HFHC) diet. Methods: Cerebral ceramide and FA profiles were determined by LC-MSMS in 15-month-old female wild-type (WT), ApoE-knockout (E0), and hE4-knockin mice fed chow or a HFHC diet for 3 months. mRNA levels …of genes involved in ceramide and FA metabolism were determined by qPCR. Results: Similar to E0, hE4 mice displayed lower cerebral total ceramide, Cer16 : 0, and Cer24 : 1 levels than WT mice on both diets. Akin to WT mice, hE4 mice had lower total and saturated FA levels on chow than E0 mice. The HFHC diet significantly increased total and saturated FA levels in hE4 mice. Chow-fed hE4 mice showed lower mRNA levels of ceramide synthase (CerS) 6, acid sphingomyelinase, and of most ceramide and FA transporters than WT and E0 mice. The HFHC diet downregulated the expression of CerSs in hE4 and WT mice, and of ceramide and FA transporters in WT mice, but not in E0 mice. Conclusion: hE4 reduced cerebral ceramide levels to levels observed in E0 mice independent of diet. The HFHC diet increased cerebral FA levels in hE4 mice. This was associated with alterations in the expression of ceramide and FA transporters specifically in hE4 mice. Show more

Keywords: Alzheimer’s disease, apolipoprotein E4, ceramides, fatty acids, high fat diet, sphingolipids

DOI: 10.3233/JAD-160739

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 769-781, 2017

Authors: Crivelli, Simone M. | Paulus, Andreas | Markus, Jozef | Bauwens, Matthias | Berkes, Dusan | De Vries, Helga E. | Mulder, Monique T. | Walter, Jochen | Mottaghy, Felix M. | Losen, Mario | Martinez-Martinez, Pilar

Article Type: Research Article

Abstract: Ceramide levels are increased in blood and brain tissue of Alzheimer’s disease (AD) patients. Since the ceramide transporter protein (CERT) is the only known protein able to mediate non-vesicular transfer of ceramide between organelle membranes, the modulation of CERT function may impact on ceramide accumulation. The competitive CERT inhibitor N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl) dodecanamide (HPA-12) interferes with ceramide trafficking. To understand the role of ceramide/CERT in AD, HPA-12 can be a useful tool to modulate ceramide trafficking. Here we first report the synthesis and in vitro properties of HPA-12 radiolabeled with fluorine-18 and present preliminary in vitro and in vivo …positron emission tomography (PET) imaging and biodistribution data. In vitro results demonstrated that the fluorination did not alter the biological properties of HPA-12 since the [fluorine-19]HPA-12, interferes with 5-DMB-ceramide trafficking in HeLa cells. Radiolabeled HPA-12, [fluorine-18]HPA-12, was obtained with a radiochemical yield of 90% and a specific activity of 73 MBq/μmol. PET imaging on wild-type mice showed hepatobiliary clearance and a brain uptake on the order of 0.3 standard uptake value (SUV) one hour post injection. Furthermore, the biodistribution data showed that after removal of the blood by intracardial perfusion, radioactivity was still measurable in the brain demonstrating that the [fluorine-18]HPA-12 crosses the blood brain barrier and is retained in the brain. Show more

Keywords: Alzheimer’s disease, ceramide, ceramide transporter protein CERT, HPA-12

DOI: 10.3233/JAD-161231

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 783-794, 2017

Authors: de Wit, Nienke M. | Snkhchyan, Hripsime | den Hoedt, Sandra | Wattimena, Darcos | de Vos, Rob | Mulder, Monique T. | Walter, Jochen | Martinez-Martinez, Pilar | Hoozemans, Jeroen J. | Rozemuller, Annemieke J. | de Vries, Helga E.

Article Type: Research Article

Abstract: Background: The majority of patients with Alzheimer’s disease (AD) exhibit amyloid-β (Aβ) deposits at the brain vasculature, a process referred to as cerebral amyloid angiopathy (CAA). In over 51% of AD cases, Aβ also accumulates in cortical capillaries, which is termed capillary CAA (capCAA). It has been postulated that the presence of capCAA in AD is a specific subtype of AD, although underlying mechanisms are not yet fully understood. Sphingolipids (SLs) are implicated in neurodegenerative disorders, including AD. However, to date it remains unknown whether alterations in the SL pathway are involved in capCAA pathogenesis and if these differ from …AD. Objective: To determine whether AD cases with capCAA have an altered SL profile compared to AD cases without capCAA. Methods: Immunohistochemistry was performed to assess the expression and localization of ceramide, acid sphingomyelinase (ASM), and sphingosine-1-phosphate receptors (S1P1, S1P3). In addition, we determined the concentrations of S1P as well as different chain-lengths of ceramides using HPLC-MS/MS. Results: Immunohistochemical analysis revealed an altered expression of ceramide, ASM, and S1P receptors by reactive astrocytes and microglial cells specifically associated with capCAA. Moreover, a shift in the balance of ceramides with different chain-lengths and S1P content is observed in capCAA. Conclusion: Here we provide evidence of a deregulated SL balance in capCAA. The increased levels of ASM and ceramide in activated glia cells suggest that the SL pathway is involved in the neuroinflammatory response in capCAA pathogenesis. Future research is needed to elucidate the role of S1P in capCAA. Show more

Keywords: Acid sphingomyelinase, Alzheimer’s disease, capillary cerebral amyloid angiopathy, ceramide, inflammation, neurodegenerative disease, sphingosine-1-phosphate

DOI: 10.3233/JAD-160551

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 795-807, 2017

Authors: Kim, Min | Nevado-Holgado, Alejo | Whiley, Luke | Snowden, Stuart G. | Soininen, Hilkka | Kloszewska, Iwona | Mecocci, Patrizia | Tsolaki, Magda | Vellas, Bruno | Thambisetty, Madhav | Dobson, Richard J.B. | Powell, John F. | Lupton, Michelle K. | Simmons, Andy | Velayudhan, Latha | Lovestone, Simon | Proitsi, Petroula | Legido-Quigley, Cristina

Article Type: Research Article

Abstract: Lipids such as ceramides and phosphatidylcholines (PC) have been found altered in the plasma of Alzheimer’s disease (AD) patients in a number of discovery studies. For this reason, the levels of 6 ceramides and 3 PCs, with different fatty acid length and saturation levels, were measured in the plasma from 412 participants (AD n  = 205, Control n  = 207) using mass spectrometry coupled with ultra-performance liquid chromatography. After this, associations with AD status, brain atrophy, and age-related effects were studied. In the plasma of AD participants, cross-sectional analysis revealed elevated levels of three ceramides (Cer16:0 p  < 0.01, Cer18:0 p  < 0.01, Cer24:1 …p  < 0.05). In addition, two PCs in AD plasma (PC36:5 p  < 0.05, PC38:6 p  < 0.05) were found to be depleted compared to the control group, with PC36:5 also associating with hippocampal atrophy (p  < 0.01). Age-specific analysis further revealed that levels of Cer16:0, Cer18:0, and Cer20:0 were associated with hippocampal atrophy only in younger participants (age < 75, p  < 0.05), while all 3 PCs did so in the older participants (age > 75, p  < 0.05). PC36:5 was associated with AD status in the younger group (p  < 0.01), while PC38:6 and 40:6 did so in the older group (p  < 0.05). In this study, elevated ceramides and depleted PCs were found in the plasma from 205 AD volunteers. Our findings also suggest that dysregulation in PC and ceramide metabolism could be occurring in different stages of AD progression. Show more

Keywords: Alzheimer’s disease, brain atrophy, ceramide, phosphatidylcholine

DOI: 10.3233/JAD-160645

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 809-817, 2017

Authors: Mielke, Michelle M. | Haughey, Norman J. | Han, Dingfen | An, Yang | Bandaru, Veera Venkata Ratnam | Lyketsos, Constantine G. | Ferrucci, Luigi | Resnick, Susan M.

Article Type: Research Article

Abstract: Background: Cellular and animal studies demonstrated relationships between sphingolipid metabolism and Alzheimer’s disease (AD) pathology. High blood ceramide levels have been shown to predict cognitive impairment and AD, but these studies had small sample sizes and did not assess differences in risk by sex or APOE genotype. Objective: To determine whether plasma ceramides and sphingomyelins were associated with risk of AD, and whether the association varied by sex and APOE genotype. Methods: Participants included 626 men and 366 women, aged 55 years and older, enrolled in the Baltimore Longitudinal Study of Aging. Plasma ceramides and sphingomyelins …were determined using quantitative analyses performed on a high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometer. Cox proportional hazards models, stratified by sex, were used to examine the relationship of plasma ceramides and sphingomyelins with risk of AD over a mean (SD) follow-up of 15.0 (7.0) years for men and 13.1 (5.9) years for women. Results: Among men, the highest tertile of most ceramides and sphingomyelins were associated with an increased risk of AD. Among women, there were no associations between any of the ceramides and risk of AD. In contrast, women in the highest tertile of most sphingomyelins had a reduced risk of AD, which was most pronounced among APOE ɛ 4 carriers. Conclusion: These results provide further evidence for the role of sphingolipid metabolism in AD and highlight the importance of considering sex and APOE genotype in assessing this relationship. Show more

Keywords: Alzheimer’s disease, ceramides, cohort study, Epidemiology, lipids, longitudinal, sex differences

DOI: 10.3233/JAD-160925

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 819-828, 2017

Authors: Saleem, Mahwesh | Herrmann, Nathan | Dinoff, Adam | Mielke, Michelle M. | Oh, Paul I. | Shammi, Prathiba | Cao, Xingshan | Venkata, Swarajya Lakshmi Vattem | Haughey, Norman J. | Lanctôt, Krista L.

Article Type: Research Article

Abstract: Background: Early subtle deficits in verbal memory, which may indicate early neural risk, are common in patients with coronary artery disease (CAD). While exercise can improve cognition, cognitive response to exercise is heterogeneous. Sphingolipids have been associated with the development and progression of CAD, and impairments in sphingolipid metabolism may play roles in neurodegeneration and in the neural adaptation response to exercise. Objective: In this study, change in plasma concentrations of sphingolipids was assessed in relation to change in verbal memory performance and in other cognitive domains among CAD subjects undertaking a 6-month cardiac rehabilitation (CR) program. …Methods: Patients with CAD (n  = 120, mean age = 64±6 y, 84% male, years of education = 16±3) underwent CR with neuropsychological assessments and blood collected at baseline, 3-, and 6-months. Z-scores based on age, gender, and education were combined for verbal memory, visuospatial memory, processing speed, executive function, and global cognition tasks to calculate cognitive domain Z-scores. Plasma sphingolipid concentrations were measured from fasting blood samples using high performance liquid chromatography coupled electrospray ionization tandem mass spectrometry (LC/MS/MS). Mixed models were used to identify sphingolipids significantly associated with performance in verbal memory and other cognitive domains, adjusting for potential confounders. Results: A decrease in ceramide C18:0 concentration was significantly associated with improvement in verbal memory performance (b [SE] = –0.51 [0.25], p  = 0.04), visuospatial memory (b [SE] = –0.44 [0.22], p  = 0.05), processing speed (b [SE] = –0.89 [0.32], p  = 0.007), and global cognition (b [SE] = –1.47 [0.59], p  = 0.01) over 6 months of CR. Conclusions: Plasma ceramide C18:0 concentrations may be a sensitive marker of cognitive response to exercise in patients with CAD. Show more

Keywords: Ceramides, cognition, coronary artery disease, exercise, memory, sphingolipids

DOI: 10.3233/JAD-161292

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 829-841, 2017

Article Type: Other

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 843-843, 2017