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.
Highlights
Alzheimer’s disease (AD) increases dramatically in patients with ischaemic stroke
Western blotting confirmed the results of the kinexus screen showing that IRS-1 and tau were phosphorylated in the presence of monomeric C-reactive protein (CRP) (mCRP) in Bovine aortic endothelial cells (BAEC) after 8 minutes
Desmond et al.[1] demonstrated a significant increased risk of dementia associated with ischaemic stroke with specific relationships to cerebral hypoxia/ischaemia
Summary
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, being able to dissociate native-CRP into inflammatory, mCRP in vivo. Native CRP can be dissociated irreversibly to form free sub-units or monomeric CRP (mCRP) which has much lower aqueous solubility, becomes tissue ECM-associated and has been shown to accumulate within tissue regions of vascular damage/inflammation, in reference to this work, accumulating in active brain neo-microvessels after ischaemic stroke[8]. This gives CRP unique properties amongst the pentraxin family. This could have implications concerning both vascular and neuronal degeneration, linked with neurodegenerative processes and in particular vascular dementia/CAA
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