Altered Sphingolipid Balance in Capillary Cerebral Amyloid Angiopathy

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

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)795-807
Number of pages13
JournalJournal of Alzheimer's Disease
Volume60
Issue number3
DOIs
Publication statusPublished - 2017

Cite this

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. / Altered Sphingolipid Balance in Capillary Cerebral Amyloid Angiopathy. In: Journal of Alzheimer's Disease. 2017 ; Vol. 60, No. 3. pp. 795-807.
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title = "Altered Sphingolipid Balance in Capillary Cerebral Amyloid Angiopathy",
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.",
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author = "{de Wit}, {Nienke M} and Hripsime Snkhchyan and {den Hoedt}, Sandra and Darcos Wattimena and {de Vos}, Rob and Mulder, {Monique T} and Jochen Walter and Pilar Martinez-Martinez and Hoozemans, {Jeroen J} and Rozemuller, {Annemieke J} and {de Vries}, {Helga E}",
year = "2017",
doi = "10.3233/JAD-160551",
language = "English",
volume = "60",
pages = "795--807",
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de Wit, NM, Snkhchyan, H, den Hoedt, S, Wattimena, D, de Vos, R, Mulder, MT, Walter, J, Martinez-Martinez, P, Hoozemans, JJ, Rozemuller, AJ & de Vries, HE 2017, 'Altered Sphingolipid Balance in Capillary Cerebral Amyloid Angiopathy' Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 795-807. https://doi.org/10.3233/JAD-160551

Altered Sphingolipid Balance in Capillary Cerebral Amyloid Angiopathy. / 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.

In: Journal of Alzheimer's Disease, Vol. 60, No. 3, 2017, p. 795-807.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Altered Sphingolipid Balance in Capillary Cerebral Amyloid Angiopathy

AU - de Wit, Nienke M

AU - Snkhchyan, Hripsime

AU - den Hoedt, Sandra

AU - Wattimena, Darcos

AU - de Vos, Rob

AU - Mulder, Monique T

AU - Walter, Jochen

AU - Martinez-Martinez, Pilar

AU - Hoozemans, Jeroen J

AU - Rozemuller, Annemieke J

AU - de Vries, Helga E

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.3233/JAD-160551

DO - 10.3233/JAD-160551

M3 - Article

VL - 60

SP - 795

EP - 807

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

SN - 1387-2877

IS - 3

ER -