Nienke M de Wit1, Hripsime Snkhchyan2, Sandra den Hoedt3, Darcos Wattimena3, Rob de Vos4, Monique T Mulder3, Jochen Walter5, Pilar Martinez-Martinez6, Jeroen J Hoozemans2, Annemieke J Rozemuller2, Helga E de Vries1. 1. Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. 2. Department of Pathology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. 3. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. 4. Laboratorium Pathology Oost Nederland, Enschede, The Netherlands. 5. Department of Neurology, University of Bonn, Bonn, Germany. 6. Department of Neuroscience, School of Mental Health and Neuroscience, Maastricht University, The Netherlands.
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.
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.
Authors: Andreas Charidimou; Gregoire Boulouis; M Edip Gurol; Cenk Ayata; Brian J Bacskai; Matthew P Frosch; Anand Viswanathan; Steven M Greenberg Journal: Brain Date: 2017-07-01 Impact factor: 13.501
Authors: Alwin Kamermans; Tom Verhoeven; Bert van Het Hof; Jasper J Koning; Lauri Borghuis; Maarten Witte; Jack van Horssen; Helga E de Vries; Merel Rijnsburger Journal: Front Immunol Date: 2019-10-04 Impact factor: 7.561
Authors: Simone M Crivelli; Qian Luo; Jo A A Stevens; Caterina Giovagnoni; Daan van Kruining; Gerard Bode; Sandra den Hoedt; Barbara Hobo; Anna-Lena Scheithauer; Jochen Walter; Monique T Mulder; Christopher Exley; Matthew Mold; Michelle M Mielke; Helga E De Vries; Kristiaan Wouters; Daniel L A van den Hove; Dusan Berkes; María Dolores Ledesma; Joost Verhaagen; Mario Losen; Erhard Bieberich; Pilar Martinez-Martinez Journal: Alzheimers Res Ther Date: 2021-02-17 Impact factor: 6.982
Authors: Nienke M de Wit; Kevin Mol; Sabela Rodríguez-Lorenzo; Helga E de Vries; Gijs Kooij Journal: Front Immunol Date: 2021-01-29 Impact factor: 7.561
Authors: Gabrielle R Phillips; Jennifer T Saville; Sarah E Hancock; Simon H J Brown; Andrew M Jenner; Catriona McLean; Maria Fuller; Kelly A Newell; Todd W Mitchell Journal: Brain Commun Date: 2021-12-23
Authors: Diana Clausznitzer; Cesar Pichardo-Almarza; Ana Lucia Relo; Jeroen van Bergeijk; Elizabeth van der Kam; Loic Laplanche; Neil Benson; Marjoleen Nijsen Journal: CPT Pharmacometrics Syst Pharmacol Date: 2018-10-08