TY - JOUR
T1 - Proteomics analysis identifies new markers associated with capillary cerebral amyloid angiopathy in Alzheimer's disease
AU - Hondius, David C.
AU - Eigenhuis, Kristel N.
AU - Morrema, Tjado H.J.
AU - van der Schors, Roel C.
AU - van Nierop, Pim
AU - Bugiani, Marianna
AU - Li, Ka Wan
AU - Hoozemans, Jeroen J.M.
AU - Smit, August B.
AU - Rozemuller, Annemieke J.M.
N1 - Funding Information:
The authors thank the Netherlands Brain Bank (Amsterdam, the Netherlands) for supplying human brain tissue. The authors want to thank Will Hermsen, University Medical Center Utrecht, for performing the immunohistochemistry on the prion tissue. This work was financially supported by Amsterdam Neuroscience and Alzheimer Nederland, grant number AN-16054. David Hondius was supported by the CAVIA project (nr. 733050202), which has been made possible by ZonMW, part of the Dutch national ‘Deltaplan for Dementia’: zonmw.nl/dementiaresearch”.
PY - 2018/6/4
Y1 - 2018/6/4
N2 - Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) deposits as plaques in the parenchyma and in the walls of cortical and leptomeningeal blood vessels of the brain called cerebral amyloid angiopathy (CAA). It is suggested that CAA type-1, which refers to amyloid deposition in both capillaries and larger vessels, adds to the symptomatic manifestation of AD and correlates with disease severity. Currently, CAA cannot be diagnosed pre-mortem and disease mechanisms involved in CAA are elusive. To obtain insight in the disease mechanism of CAA and to identify marker proteins specifically associated with CAA we performed a laser dissection microscopy assisted mass spectrometry analysis of post-mortem human brain tissue of (I) AD cases with only amyloid deposits in the brain parenchyma and no vascular related amyloid, (II) AD cases with severe CAA type-1 and no or low numbers of parenchymal amyloid deposits and (III) cognitively healthy controls without amyloid deposits. By contrasting the quantitative proteomics data between the three groups, 29 potential CAA-selective proteins were identified. A selection of these proteins was analysed by immunoblotting and immunohistochemistry to confirm regulation and to determine protein localization and their relation to brain pathology. In addition, specificity of these markers in relation to other small vessel diseases including prion CAA, CADASIL, CARASAL and hypertension related small vessel disease was assessed using immunohistochemistry.Increased levels of clusterin (CLU), apolipoprotein E (APOE) and serum amyloid P-component (APCS) were observed in AD cases with CAA. In addition, we identified norrin (NDP) and collagen alpha-2(VI) (COL6A2) as highly selective markers that are clearly present in CAA yet virtually absent in relation to parenchymal amyloid plaque pathology. NDP showed the highest specificity to CAA when compared to other small vessel diseases. The specific changes in the proteome of CAA provide new insight in the pathogenesis and yields valuable selective biomarkers for the diagnosis of CAA.
AB - Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) deposits as plaques in the parenchyma and in the walls of cortical and leptomeningeal blood vessels of the brain called cerebral amyloid angiopathy (CAA). It is suggested that CAA type-1, which refers to amyloid deposition in both capillaries and larger vessels, adds to the symptomatic manifestation of AD and correlates with disease severity. Currently, CAA cannot be diagnosed pre-mortem and disease mechanisms involved in CAA are elusive. To obtain insight in the disease mechanism of CAA and to identify marker proteins specifically associated with CAA we performed a laser dissection microscopy assisted mass spectrometry analysis of post-mortem human brain tissue of (I) AD cases with only amyloid deposits in the brain parenchyma and no vascular related amyloid, (II) AD cases with severe CAA type-1 and no or low numbers of parenchymal amyloid deposits and (III) cognitively healthy controls without amyloid deposits. By contrasting the quantitative proteomics data between the three groups, 29 potential CAA-selective proteins were identified. A selection of these proteins was analysed by immunoblotting and immunohistochemistry to confirm regulation and to determine protein localization and their relation to brain pathology. In addition, specificity of these markers in relation to other small vessel diseases including prion CAA, CADASIL, CARASAL and hypertension related small vessel disease was assessed using immunohistochemistry.Increased levels of clusterin (CLU), apolipoprotein E (APOE) and serum amyloid P-component (APCS) were observed in AD cases with CAA. In addition, we identified norrin (NDP) and collagen alpha-2(VI) (COL6A2) as highly selective markers that are clearly present in CAA yet virtually absent in relation to parenchymal amyloid plaque pathology. NDP showed the highest specificity to CAA when compared to other small vessel diseases. The specific changes in the proteome of CAA provide new insight in the pathogenesis and yields valuable selective biomarkers for the diagnosis of CAA.
KW - Alzheimer’s disease
KW - Amyloid beta
KW - Biomarker
KW - Cerebral amyloid angiopathy
KW - Human brain
KW - Laser microdissection
KW - Post-mortem tissue
KW - Proteomics
UR - https://www.scopus.com/pages/publications/85059374938
U2 - 10.1186/s40478-018-0540-2
DO - 10.1186/s40478-018-0540-2
M3 - Article
C2 - 29860944
AN - SCOPUS:85059374938
SN - 2051-5960
VL - 6
JO - Acta neuropathologica communications
JF - Acta neuropathologica communications
IS - 1
ER -