Recent research has shown precise mechanisms of which amyloid beta peptide – the protein associated with Alzheimer’s disease onset and progression – has detrimental effects on brain endothelial vascular cells.
The multi-centre group of scientists behind the study discovered that amyloid-β causes endoplasmic reticulum stress (ERS) in rat brain endothelial cells (bEND.3), subsequently leading to the dysregulation of key proteins and vascular damage.
Neurovascular dysfunction has been shown to be a component of Alzheimer’s disease neurodegeneration, yet the specific mechanisms leading to this have remained relatively unknown. This study has established that amyloid-β induced ERS upregulates cell death related proteins (pro-apoptotic) and downregulates key tight junction proteins which are crucial to healthy cognition in the blood-brain barrier (BBB).
The ERS damage inflicted by amyloid-β is initiated by activation of receptors for advanced glycation end-products (RAGE), which subsequently mediates and prompts endoplasmic reticulum stress.
The Blood-Brain Barrier
The brain is a sensitive organ which is protected from potentially damaging cells, proteins, and compounds by the highly selective permeability of the blood-brain barrier. This strict regulation is maintained by cells of the BBB and crucially the protein junctions which interlink the endothelial cells.
A subtype of these inter-cellular protein junctions called tight junctions are perhaps the most crucial to avoiding foreign elements entering the brain tissue, and it is these tight junctions which are downregulated from endothelial interaction with amyloid-β.
Consequences of BBB disruption range from the damaging infiltration of foreign cells and compounds, to a reduction in overall blood flow to the brain. Infiltration of foreign elements to the brain causes the activation of glial cells – the immune cells of the brain – and immune cells from the blood, resulting in damaging inflammation and subsequent cell death.
When coupled with the reduction in blood flow to the brain, BBB dysfunction forms a substantial component of Alzheimer’s disease pathology. Reduction in blood flow to the brain is a common component of vascular dementia and is commonly a consequence of stroke.
Vascular Significance In Alzheimer’s Disease
This study highlights the importance of vascular components to Alzheimer’s disease pathology. Up until recent years the focus of treatment targets for Alzheimer’s disease has centred around reduction in amyloid-β to reduce the amount of toxic plaques that damage neurons.
This research elucidates the mechanism of damage induced by amyloid-β on vasculature in the brain, adding to the previously known mechanisms of amyloid-β and adverse effects.
Endothelial Junctions And Neurodegenerative Disease
Endothelial disruption is not just a consequence of Alzheimer’s disease, with multiple sclerosis and Parkinson’s disease both having an element of BBB dysfunction in their pathologies. This was highlighted in recent studies of multiple sclerosis, where endothelial tight junctions were shown to be disrupted as a consequence of the disease.
These studies exemplify the importance of vasculature in the brain and could see endothelial cells as a target to prevent or treat neurodegenerative diseases in future.
Wenjing Chen, Yuanjin Chan, Wenbin Wan, Yaming Lia, Chunyan Zhang Aβ1-42 induces cell damage via RAGE-dependent endoplasmic reticulum stress in bEnd.3 cells Experimental Cell Research. 14 November 2017 https://doi.org/10.1016/j.yexcr.2017.11.005
Author: Geoffrey Potjewyd; Regenerative Medicine & Neuroscience PhD student at the University of Manchester. Image: Phaeton1, CC BY-SA 3.0