Clusterin/Apolipoprotein J immunoreactivity is associated with white matter damage in cerebral small vessel diseases.
OBJECTIVE
Brain 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.


METHODS
Post-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.


RESULTS
Immunostaining 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.


CONCLUSIONS
Our 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.
Neurovascular Research Group, Institute for Ageing & Health, Newcastle University, Newcastle Upon Tyne, UK.
Lucinda
http://orcid.org/0000-0001-9192-1072
L
Craggs
Neurovascular Research Group, Institute for Ageing & Health, Newcastle University, Newcastle Upon Tyne, UK.
Julie
J
Taylor
Neurovascular Research Group, Institute for Ageing & Health, Newcastle University, Newcastle Upon Tyne, UK.
Janet Y
JY
Slade
Neurovascular Research Group, Institute for Ageing & Health, Newcastle University, Newcastle Upon Tyne, UK.
Aiqing
A
Chen
Institute of Neuropathology, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
Christian
C
Hagel
Department of Molecular Neurobiology, Institute of Experimental Medicine, University of Kiel, Kiel, Germany.
Gregor
G
Kuhlenbaeumer
Institute of Neuroscience and Physiology, Salhgrenska Academy at Göteborg University, Goteborg, Sweden.
Anne
A
Borjesson-Hanson
Department of Clinical Neurosciences, Karolinska Institute, Huddinge Hospital, Stockholm, Sweden.
Matti
M
Viitanen
Department of Neuropathology, Helsinki University, Helsinki, Finland.
Hannu
H
Kalimo
Univ Lille Nord de France, Excellence Laboratory DISTALZ, EA1046, Histology and Pathology Department, Lille University Hospital, Lille, France.
Vincent
V
Deramecourt
Neurovascular Research Group, Institute for Ageing & Health, Newcastle University, Newcastle Upon Tyne, UK.
Arthur E
AE
Oakley
Neurovascular Research Group, Institute for Ageing & Health, Newcastle University, Newcastle Upon Tyne, UK.
Raj N
RN
Kalaria
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001344:Autopsy; D001921:Brain / Q000378:metabolism / Q000473:pathology; D059345:Cerebral Small Vessel Diseases / Q000378:metabolism* / Q000473:pathology*; D051152:Clusterin / Q000032:analysis / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D066127:White Matter / Q000378:metabolism / Q000473:pathology*
C495242:CLU protein, human; D051152:Clusterin
Alzheimer's disease; CADASIL; cerebral amyloid angiopathy; cerebrovascular disease; clusterin; granular osmiophilic material