Abstract
AimBrain clusterin is known to be associated with the amyloid‐β deposits in Alzheimer's disease (AD). We assessed the distribution of clusterin immunoreactivity in cerebrovascular disorders, particularly focusing on white matter changes in small vessel diseases.MethodsPost‐mortem brain tissues from the frontal or temporal lobes of a total of 70 subjects with various disorders including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral amyloid angiopathy (CAA) and AD were examined using immunohistochemistry and immunofluorescence. We further used immunogold electron microscopy to study clusterin immunoreactivity in extracellular deposits in CADASIL.ResultsImmunostaining with clusterin antibodies revealed strong localization in arterioles and capillaries, besides cortical neurones. We found that clusterin immunostaining was significantly increased in the frontal white matter of CADASIL and pontine autosomal dominant microangiopathy and leukoencephalopathy subjects. In addition, clusterin immunostaining correlated with white matter pathology severity scores. Immunostaining in axons ranged from fine punctate deposits in single axons to larger confluent areas with numerous swollen axon bulbs, similar to that observed with known axon damage markers such as non‐phosphorylated neurofilament H and the amyloid precursor protein. Immunofluorescence and immunogold electron microscopy experiments showed that whereas clusterin immunoreactivity was closely associated with vascular amyloid‐β in CAA, it was lacking within the granular osmiophilic material immunolabelled by NOTCH3 extracelluar domain aggregates found in CADASIL.ConclusionsOur results suggest a wider role for clusterin associated with white matter damage in addition to its ability to chaperone proteins for clearance via the perivascular drainage pathways in several disease states.
Highlights
Clusterin, known, as apolipoprotein J, is a highly conserved 78–80 kDa heterodimeric glycoprotein expressed in a wide variety of tissues and cells, encoded by a single copy gene on chromosome 8 in man [1]
Using Kruskal– Wallis H tests, we found pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL) brain tissues to reveal significantly greater %A of clusterin immunostaining in the white matter (WM) (Figure 2A) compared with the other groups, followed by Swedish hMID, CADASIL and young control groups
Kruskal– Wallis H test revealed significant differences in clusterin axon score between the groups (P < 0.05), where we found significant increases in clusterin immunostaining within damaged axons in CADASIL compared with young controls despite their similar age (P < 0.05, Mann–Whitney U test) (Figure 3F)
Summary
Known, as apolipoprotein J, is a highly conserved 78–80 kDa heterodimeric glycoprotein expressed in a wide variety of tissues and cells, encoded by a single copy gene on chromosome 8 in man [1]. This gene encodes a 449 amino acid precursor polypeptide which is cleaved to form the mature secreted clusterin protein; a heterodimeric glycoprotein consisting of two disulphide linked α- and β subunits which functions to scavenge and chaperone damaged proteins in the extracellular compartment of tissues [1,2]. Studies measuring protein levels in cerebrospinal fluid (CSF) revealed elevated CSF clusterin in AD cases compared with controls [10], and a study of nondemented and mild cognitive impairment patients revealed increased CSF clusterin was related to amyloid β-associated brain atrophy [11]
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