Monomeric C-reactive protein--a key molecule driving development of Alzheimer's disease associated with brain
M Slevin1,2,3, S Matou1, Y Zeinolabediny1
1School of Healthcare Science, John Dalton Building, Manchester Metropolitan University, Chester Street, Manchester, M1 5GD, UK.
Abstract:
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.
Insights
Monomeric C-reactive protein (mCRP) drives dementia after ischemic stroke by damaging neurons and promoting Alzheimer's disease pathology. Clearing mCRP may reduce dementia risk following stroke.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Ischemic stroke significantly increases Alzheimer's disease (AD) risk.
- Monomeric C-reactive protein (mCRP) is found in ischemic tissue and can promote inflammation.
Purpose of the Study:
- To investigate the role of mCRP in the development of cognitive deficits and AD pathology after ischemic stroke.
Main Methods:
- mCRP was injected into mouse hippocampus; behavioral tests, immunohistochemistry, phospho-arrays, Western blotting, and in vitro assays were performed.
- Human AD/stroke patient tissues were analyzed for mCRP co-localization with AD markers.
Main Results:
- In mice, mCRP caused cognitive deficits, neuronal damage (p-tau), amyloid plaque association, and activated signaling pathways (p-IRS-1, p-ERK1/2).
- mCRP increased vascular permeability, induced angiogenesis, and promoted tau aggregation in vitro.
- Human studies showed mCRP co-localizes with AD pathology in stroke patients.
Conclusions:
- mCRP may be a key factor in post-stroke dementia development.
- Targeting mCRP could be a therapeutic strategy to mitigate dementia risk after ischemic stroke.
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