Amyloid-β Biochemistry as a Cause of Blood-Brain Barrier Leakage in Alzheimer’s Disease – Fight Aging!

Alzheimer’s disease is a complex degenerative failure of the brain, with various mechanisms at play such as amyloid-β aggregation, chronic inflammation, and vascular dysfunction. Researchers are challenged by the interconnectedness of these mechanisms, making it difficult to isolate and target them for treatment. Most Alzheimer’s patients exhibit cerebral amyloid angiopathy, leading to dysfunction and leakage of microvessels. A new study delves into the mechanisms by which amyloid-β aggregation causes blood-brain barrier dysfunction, highlighting the multifactorial nature of Alzheimer’s disease. The amyloid cascade hypothesis has been the most influential paradigm in understanding AD pathology, however, the lack of clinical success in inhibiting or clearing toxic Aβ aggregates suggests the disease’s pathophysiology is multifactorial. In addition to Aβ amyloidogenesis, other factors such as tauopathies and neuroimmune activation are also responsible for neurodegeneration in AD. The correlation between AD and cerebral amyloid angiopathy suggests an important role of endothelial integrity in the development of AD pathogenesis, as evidenced by observations of cerebral endothelial dysfunction and microvascular injury induced by Aβ. The study reveals amyloid protein-induced endothelial leakiness in human microvascular endothelial monolayers and mouse cerebral vasculature, proposing a paradigm for elucidating the vascular permeation, systemic spread, and cross-seeding of amyloid proteins that underlie the pathogenesis of AD and Parkinson’s disease.