Fig. 6

The role of BBB dysfunction in the progression of neurodegenerative disease. BBB dysfunction is associated with many late stage neurodegenerative diseases and is thought to be a consequence of accumulation of toxic aggregates and neuronal cell death. BBB dysfunction can lead to entry of blood components and compromised nutrient transport, providing positive feedback for disease progression. We propose that mutations associated with neurodegenerative diseases can independently lead to accumulation of defects in the blood–brain barrier, ultimately resulting in increased paracellular permeability and/or compromised transport systems (e.g. efflux of non-essential molecules or decreased nutrient transport). Prior to the onset of measurable changes in barrier function, accumulation of defects in the BBB may occur independently of or in parallel with gain of toxic function in neurons, or other cell types in the brain