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Cerebral amyloid angiopathy (CAA) is frequently observed in Alzheimer��?s disease (AD) and is marked by deposition of amyloid
beta (A�?²) in leptomeningeal and cortical brain vasculature. In over 40% of AD cases, A�?² accumulates in cortical capillaries, a
phenomenon referred to as capillary CAA (capCAA), which is associated with loss of tight junction proteins and a reduced function
of P-glycoprotein, indicating impaired function of the blood brain barrier (BBB) and decreased transport of amyloid beta across the
BBB. Increasing evidence suggests that an altered sphingolipid (SL) metabolism contributes to Alzheimer's disease. However, to date
it remains unknown if alteration of the SL pathway is involved in capCAA pathogenesis. In this study we set out to investigate the
alterations of the different players of the SL pathway in capCAA. Expression and localization of ceramide, sphingosine-1-phosphate
(S1P) receptors (S1P1, S1P3) and the enzyme involved in ceramide production, acid sphingomyelinase (ASM), were assessed using
immunohistochemistry on post-mortem tissue from the occipital cortex of non-neurological controls, AD and severe capCAA cases.
Increased immunoreactivity for ceramide, S1P3, S1P1 and ASM was observed in capCAA cases compared to non-neurological
controls and AD cases. Immunoreactivity for ceramide and S1P3 was primarily observed in astrocytes, whereas immunoreactivity
for S1P1 and ASM was observed in microglia. In capCAA, all SL markers showed high levels of immunoreactivity around amyloidladen
capillaries and correlated with the presence GFAP and HLA-DR as markers for glial activation. We find increased presence
of SL pathway markers in AD cases with capCAA. The increased presence of these markers in glial cells associated amyloid-laden
capillaries, suggests that the SL pathway is involved in the neuroinflammatory response in capCAA pathogenesis. Future studies are
needed to address the functional role of the SL pathway in capCAA pathology.