Abstract
A key step in plasma HDL maturation from discoidal to spherical particles is the esterification of cholesterol to cholesteryl ester, which is catalyzed by LCAT. HDL-like lipoproteins in cerebrospinal fluid (CSF) are also spherical, whereas nascent lipoprotein particles secreted from astrocytes are discoidal, suggesting that LCAT may play a similar role in the CNS. In plasma, apoA-I is the main LCAT activator, while in the CNS, it is believed to be apoE. apoE is directly involved in the pathological progression of Alzheimer's disease, including facilitating β-amyloid (Aβ) clearance from the brain, a function that requires its lipidation by ABCA1. However, whether apoE particle maturation by LCAT is also required for Aβ clearance is unknown. Here we characterized the impact of LCAT deficiency on CNS lipoprotein metabolism and amyloid pathology. Deletion of LCAT from APP/PS1 mice resulted in a pronounced decrease of apoA-I in plasma that was paralleled by decreased apoA-I levels in CSF and brain tissue, whereas apoE levels were unaffected. Furthermore, LCAT deficiency did not increase Aβ or amyloid in APP/PS1 LCAT(-/-) mice. Finally, LCAT expression and plasma activity were unaffected by age or the onset of Alzheimer's-like pathology in APP/PS1 mice. Taken together, these results suggest that apoE-containing discoidal HDLs do not require LCAT-dependent maturation to mediate efficient Aβ clearance.
Highlights
A key step in plasma HDL maturation from discoidal to spherical particles is the esterification of cholesterol to cholesteryl ester, which is catalyzed by LCAT
In the CNS, we have previously shown that LCAT is secreted by astrocytes and is capable of esterifying free cholesterol (FC) contained on glial-derived nascent apoE-containing particles [47]. apoE is hypothesized to be the major LCAT activator in the CNS, as apoE is sufficient to stimulate esterification of endogenous cholesterol in glial-conditioned media [39]. apoA-I, which is not synthesized within the CNS but is found in cerebrospinal fluid (CSF), is capable of esterifying cholesterol using glial-derived LCAT [47]
As there has been a single report of decreased CSF LCAT activity in human Alzheimer’s disease (AD) subjects [42], we first determined whether age and/or the presence of A deposits impacts LCAT expression or activity in APP/PS1 mice
Summary
A key step in plasma HDL maturation from discoidal to spherical particles is the esterification of cholesterol to cholesteryl ester, which is catalyzed by LCAT. ApoE is directly involved in the pathological progression of Alzheimer’s disease, including facilitating -amyloid (A) clearance from the brain, a function that requires its lipidation by ABCA1. LCAT expression and plasma activity were unaffected by age or the onset of Alzheimer’s-like pathology in APP/PS1 mice. Taken together, these results suggest that apoEcontaining discoidal HDLs do not require LCAT-dependent maturation to mediate efficient A clearance.—Stukas, S., L. It is well-established that amyloid burden in humans follows an isoform-dependent pattern of apoE4>apoE3>apoE2 [4,5,6]. It is important to note, that apoE isoforms, levels, and lipidation status are all important variables
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