Altered Sphingolipid Balance in Capillary Cerebral Amyloid Angiopathy

Issue title: Mini-Forum on Sphingolipids in Alzheimer’s Disease and Related Disorders

Guest editors: Michelle Mielke and Pilar Martinez

Article type: Research Article

Authors: de Wit, Nienke M.^{a; 1; *} | Snkhchyan, Hripsime^{b; 1} | den Hoedt, Sandra^c | Wattimena, Darcos^c | de Vos, Rob^d | Mulder, Monique T.^c | Walter, Jochen^e | Martinez-Martinez, Pilar^f | Hoozemans, Jeroen J.^b | Rozemuller, Annemieke J.^b | de Vries, Helga E.^a

Affiliations: [a] Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands | [b] Department of Pathology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands | [c] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands | [d] Laboratorium Pathology Oost Nederland, Enschede, The Netherlands | [e] Department of Neurology, University of Bonn, Bonn, Germany | [f] Department of Neuroscience, School of Mental Health and Neuroscience, Maastricht University, The Netherlands

Correspondence: [*] Correspondence to: Nienke de Wit, MSc, VU University Medical Center, Department of Molecular Cell Biology and Immu-nology, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Tel.: +31 20 444 8080; E-mail: n.dewit1@vumc.nl.

Note: [1] These authors contributed equally to this work.

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.

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

DOI: 10.3233/JAD-160551

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