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Clusterin levels are increased in Alzheimer's disease and influence the regional distribution of Aβ.

ABSTRACT: Clusterin, also known as apoJ, is a lipoprotein abundantly expressed within the CNS. It regulates Aβ fibril formation and toxicity and facilitates amyloid-β (Aβ) transport across the blood-brain barrier. Genome-wide association studies have shown variations in the clusterin gene (CLU) to influence the risk of developing sporadic Alzheimer's disease (AD). To explore whether clusterin modulates the regional deposition of Aβ, we measured levels of soluble (NP40-extracted) and insoluble (guanidine-HCl-extracted) clusterin, Aβ40 and Aβ42 by sandwich ELISA in brain regions with a predilection for amyloid pathology-mid-frontal cortex (MF), cingulate cortex (CC), parahippocampal cortex (PH), and regions with little or no pathology-thalamus (TH) and white matter (WM). Clusterin level was highest in regions with plaque pathology (MF, CC, PH and PC), approximately mirroring the regional distribution of Aβ. It was significantly higher in AD than controls, and correlated positively with Aβ42 and insoluble Aβ40. Soluble clusterin level rose significantly with severity of cerebral amyloid angiopathy, and in MF and PC regions was highest in APOE ɛ4 homozygotes. In the TH and WM (areas with little amyloid pathology) clusterin was unaltered in AD and did not correlate with Aβ level. There was a significant positive correlation between the concentration of clusterin and the regional levels of insoluble Aβ42; however, the molar ratio of clusterin : Aβ42 declined with insoluble Aβ42 level in a region-dependent manner, being lowest in regions with predilection for Aβ plaque pathology. Under physiological conditions, clusterin reduces aggregation and promotes clearance of Aβ. Our findings indicate that in AD, clusterin increases, particularly in regions with most abundant Aβ, but because the increase does not match the rising level of Aβ42, the molar ratio of clusterin : Aβ42 in those regions falls, probably contributing to Aβ deposition within the tissue.

SUBMITTER: Miners JS

PROVIDER: S-EPMC8029153 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundClusterin is a multifunctional protein, which is associated with the pathogenesis and the development of Alzheimer's disease (AD). Compared with normal controls, inconsistent results have yielded in previous studies for concentration of cerebrospinal fluid (CSF) clusterin in AD patients. We explored CSF clusterin levels in different pathological processes of AD.MethodsFollowing the National Institute on Aging-Alzheimer's Association (NIA-AA) criteria, we employed on the levels of CSF Aβ42(A), phosphorylated-Tau (T), and total-tau (N). Based on previously published cutoffs and the close correlation between CSF p-tau and t-tau, 276 participants from the publicly available ADNI database with CSF biomarkers were divided into four groups: A-(TN)- (normal Aβ42 and normal p-tau and t-tau; n = 50), A+(TN)- (abnormal Aβ42 and normal p-tau and t-tau; n = 39), A+(TN) + (abnormal Aβ42 and abnormal p-tau or t-tau; n = 147), A-(TN) + (normal Aβ42 and abnormal p-tau or t-tau; n = 40). To assess CSF clusterin levels in AD continuum, intergroup differences in four groups were compared. Pairwise comparisons were conducted as appropriate followed by Bonferroni post hoc analyses. To further study the relationships between CSF clusterin levels and AD core pathological biomarkers, we employed multiple linear regression method in subgroups.ResultsCompared with the A-(TN)- group, CSF clusterin levels were decreased in A+ (TN)- group (P = 0.002 after Bonferroni correction), but increased in the A+(TN) + group and the A-(TN) + group (both P < 0.001 after Bonferroni correction). Moreover, we found CSF clusterin levels are positively associated with CSF Aβ42 (β = 0.040, P < 0. 001), CSF p-tau (β = 0.325, P < 0.001) and CSF t-tau (β = 0.346, P < 0.001).ConclusionsOur results indicated that there are differences levels of CSF clusterin in different stages of AD pathology. The CSF clusterin level decreased at the early stage are related to abnormal Aβ pathology; and the increased levels are associated with tau pathology and neurodegeneration.

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Clusterin levels are increased in Alzheimer's disease and influence the regional distribution of Aβ.

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