Clusterin/Apolioprotein J immunoreactivity is associated with white matter damage in cerebral small vessel diseases

TY - JOUR

T1 - Clusterin/Apolioprotein J immunoreactivity is associated with white matter damage in cerebral small vessel diseases

AU - Craggs, L J L

AU - Taylor, J L

AU - Slade, J Y

AU - Chen, A

AU - Hagel, C

AU - Kuhlenbaeumer, G

AU - Borjesson-Hanson, A

AU - Viitanen, M

AU - Kalimo, H

AU - Deramecourt, V

AU - Oakley, A E

AU - Kalaria, R N

N1 - This article is protected by copyright. All rights reserved.

PY - 2016/2

Y1 - 2016/2

N2 - AIM: 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 localisation in arterioles and capillaries, besides cortical neurons. 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.

AB - AIM: 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 localisation in arterioles and capillaries, besides cortical neurons. 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.

U2 - 10.1111/nan.12248

DO - 10.1111/nan.12248

M3 - SCORING: Journal article

C2 - 25940137

VL - 42

SP - 194

EP - 209

JO - NEUROPATH APPL NEURO

JF - NEUROPATH APPL NEURO

SN - 0305-1846

IS - 2

ER -