Monomeric C-reactive protein--a key molecule driving development of Alzheimer's disease associated with brain ischaemia?
Alzheimer's disease (AD) increases dramatically in patients with ischaemic stroke. Monomeric C-reactive protein (mCRP) appears in the ECM of ischaemic tissue after stroke, associating with microvasculature, neurons and AD-plaques, Aβ, also, being able to dissociate native-CRP into inflammatory, mCRP in vivo. Here, mCRP injected into the hippocampal region of mice was retained within the retrosplenial tract of the dorsal 3rd ventrical and surrounding major vessels. Mice developed behavioural/cognitive deficits within 1 month, concomitant with mCRP staining within abnormal looking neurons expressing p-tau and in beta-amyloid 1-42-plaque positive regions. mCRP co-localised with CD105 in microvessels suggesting angiogenesis. Phospho-arrays/Western blotting identified signalling activation in endothelial cells and neurons through p-IRS-1, p-Tau and p-ERK1/2-which was blocked following pre-incubation with mCRP-antibody. mCRP increased vascular monolayer permeability and gap junctions, increased NCAM expression and produced haemorrhagic angiogenesis in mouse matrigel implants. mCRP induced tau244-372 aggregation and assembly in vitro. IHC study of human AD/stroke patients revealed co-localization of mCRP with Aβ plaques, tau-like fibrils and IRS-1/P-Tau positive neurons and high mCRP-levels spreading from infarcted core regions matched reduced expression of Aβ/Tau. mCRP may be responsible for promoting dementia after ischaemia and mCRP clearance could inform therapeutic avenues to reduce the risk of future dementia.
School of Healthcare Science, John Dalton Building, Manchester Metropolitan University, Chester Street, Manchester, M1 5GD, UK.|University of Medicine and Pharmacy, Targu Mures, Romania.|Department of Pathology/Medicine, Griffith University, Brisbane, Australia.
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Slevin
School of Healthcare Science, John Dalton Building, Manchester Metropolitan University, Chester Street, Manchester, M1 5GD, UK.
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Matou
School of Healthcare Science, John Dalton Building, Manchester Metropolitan University, Chester Street, Manchester, M1 5GD, UK.
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Zeinolabediny
Instituto De Investigaciones Biomedicas De Barcelona, CSIC, Barcelona, Spain.
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Corpas
School of Healthcare Science, John Dalton Building, Manchester Metropolitan University, Chester Street, Manchester, M1 5GD, UK.
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Weston
School of Healthcare Science, John Dalton Building, Manchester Metropolitan University, Chester Street, Manchester, M1 5GD, UK.
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Liu
School of Healthcare Science, John Dalton Building, Manchester Metropolitan University, Chester Street, Manchester, M1 5GD, UK.
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Boras
Neurological Service, San Camillo de' Lellis General Hospital, Rieti, Italy.
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Di Napoli
Department of Pathology/Medicine, Griffith University, Brisbane, Australia.
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Petcu
Instituto De Investigaciones Biomedicas De Barcelona, CSIC, Barcelona, Spain.
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Sarroca
Clinic of Neurology, Medical University Greifswald, Germany.
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Popa-Wagner
Department of Neuropathology, Institute of Clinical Neurosciences, School of Clinical Sciences, University of Bristol, Bristol, BS16 1LE, UK.
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Love
CSIC-ICCC, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.
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Font
Acphazin, Inc., Deerfield, Illinois, USA.
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Potempa
College of Applied Medical Science, Al Majmaah University, Majmaah City, Kingdom of Saudi Arabia P.O Box 66.
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Al-Baradie
Instituto De Investigaciones Biomedicas De Barcelona, CSIC, Barcelona, Spain.
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Sanfeliu
Instituto De Investigaciones Biomedicas De Barcelona, CSIC, Barcelona, Spain.
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Revilla
CSIC-ICCC, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.
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Badimon
Hospital Universitari Mútua de Terrassa, Department of Neurology, Terrassa (Barcelona), Spain.
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Krupinski
D000544:Alzheimer Disease / Q000150:complications* / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002545:Brain Ischemia / Q000150:complications* / Q000378:metabolism*; D018450:Disease Progression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism*
D015415:Biomarkers; C071581:CRP protein, human; D011971:Receptors, Immunologic