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

Lucinda J L Craggs, Julie L. Taylor, Janet Y. Slade, Aiqing Chen, Christian Hagel, Gregor Kuhlenbaeumer, Anne Borjesson-Hanson, Matti Viitanen, Hannu Kalimo, Vincent Deramecourt, Arthur E. Oakley, Raj N. Kalaria

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Abstract

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 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.

LanguageEnglish
Pages194-209
Number of pages16
JournalNeuropathology and Applied Neurobiology
Volume42
Issue number2
Early online date4 May 2015
DOIs
Publication statusPublished - 1 Feb 2016
Externally publishedYes

Fingerprint

Cerebral Small Vessel Diseases
Clusterin
CADASIL
Axons
Cerebral Amyloid Angiopathy
Fluorescent Antibody Technique
Electron Microscopy
Alzheimer Disease
Leukoencephalopathies
Cerebrovascular Disorders
Aptitude
Intermediate Filaments
White Matter
Amyloid beta-Protein Precursor
Amyloid Plaques
Brain
Arterioles
Frontal Lobe
Temporal Lobe
Amyloid

Cite this

Craggs, L. J. L., Taylor, J. L., Slade, J. Y., Chen, A., Hagel, C., Kuhlenbaeumer, G., ... Kalaria, R. N. (2016). Clusterin/Apolipoprotein J immunoreactivity is associated with white matter damage in cerebral small vessel diseases. Neuropathology and Applied Neurobiology, 42(2), 194-209. https://doi.org/10.1111/nan.12248
Craggs, Lucinda J L ; Taylor, Julie L. ; Slade, Janet Y. ; Chen, Aiqing ; Hagel, Christian ; Kuhlenbaeumer, Gregor ; Borjesson-Hanson, Anne ; Viitanen, Matti ; Kalimo, Hannu ; Deramecourt, Vincent ; Oakley, Arthur E. ; Kalaria, Raj N. / Clusterin/Apolipoprotein J immunoreactivity is associated with white matter damage in cerebral small vessel diseases. In: Neuropathology and Applied Neurobiology. 2016 ; Vol. 42, No. 2. pp. 194-209.
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abstract = "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 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.",
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Craggs, LJL, Taylor, JL, Slade, JY, Chen, A, Hagel, C, Kuhlenbaeumer, G, Borjesson-Hanson, A, Viitanen, M, Kalimo, H, Deramecourt, V, Oakley, AE & Kalaria, RN 2016, 'Clusterin/Apolipoprotein J immunoreactivity is associated with white matter damage in cerebral small vessel diseases', Neuropathology and Applied Neurobiology, vol. 42, no. 2, pp. 194-209. https://doi.org/10.1111/nan.12248

Clusterin/Apolipoprotein J immunoreactivity is associated with white matter damage in cerebral small vessel diseases. / Craggs, Lucinda J L; Taylor, Julie L.; Slade, Janet Y.; Chen, Aiqing; Hagel, Christian; Kuhlenbaeumer, Gregor; Borjesson-Hanson, Anne; Viitanen, Matti; Kalimo, Hannu; Deramecourt, Vincent; Oakley, Arthur E.; Kalaria, Raj N.

In: Neuropathology and Applied Neurobiology, Vol. 42, No. 2, 01.02.2016, p. 194-209.

Research output: Contribution to journalArticle

TY - JOUR

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

AU - Craggs, Lucinda J L

AU - Taylor, Julie L.

AU - Slade, Janet Y.

AU - Chen, Aiqing

AU - Hagel, Christian

AU - Kuhlenbaeumer, Gregor

AU - Borjesson-Hanson, Anne

AU - Viitanen, Matti

AU - Kalimo, Hannu

AU - Deramecourt, Vincent

AU - Oakley, Arthur E.

AU - Kalaria, Raj N.

PY - 2016/2/1

Y1 - 2016/2/1

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 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.

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 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.

KW - Alzheimer's disease

KW - CADASIL

KW - Cerebral amyloid angiopathy

KW - Cerebrovascular disease

KW - Clusterin

KW - Granular osmiophilic material

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