Selective loss of cortical endothelial tight junction proteins during Alzheimer’s disease progression

Abstract

While the accumulation and aggregation of amyloid-β and tau are central events in the pathogenesis of Alzheimer s disease, there is increasing evidence that cerebrovascular pathology is also abundant in Alzheimer s disease brains. In brain capillaries, endothelial cells are connected closely with one another through transmembrane tight junction proteins forming the blood-brain barrier. Because the blood-brain barrier tightly regulates the exchange of molecules between brain and blood and maintains brain homeostasis, its impairment is increasingly recognized as a critical factor contributing to Alzheimer s disease pathogenesis. However, the pathological relationship between blood-brain barrier properties and Alzheimer s disease progression in the human brain is not fully understood. In this study, we show that the loss of cortical tight junction proteins is a common event in Alzheimer s disease, and is correlated with synaptic degeneration. By quantifying the amounts of major tight junction proteins, claudin-5 and occludin, in 12 brain regions dissected from post-mortem brains of normal ageing (n = 10), pathological ageing (n = 14) and Alzheimer s disease patients (n = 19), we found that they were selectively decreased in cortical areas in Alzheimer s disease. Cortical tight junction proteins were decreased in association with the Braak neurofibrillary tangle stage. There was also a negative correlation between the amount of tight junction proteins and the amounts of insoluble Alzheimer s disease-related proteins, in particular amyloid-β40, in cortical areas. In addition, the amount of tight junction proteins in these areas correlated positively with those of synaptic markers. Thus, loss of cortical tight junction proteins in Alzheimer s disease is associated with insoluble amyloid-β40 and loss of synaptic markers. Importantly, the positive correlation between claudin-5 and synaptic markers, in particular synaptophysin, was present independent of insoluble amyloid-β40, amyloid-β42 and tau values, suggesting that loss of cortical tight junction proteins and synaptic degeneration is present, at least in part, independent of insoluble Alzheimer s disease-related proteins. Collectively, these results indicate that loss of tight junction proteins occurs predominantly in the neocortex during Alzheimer s disease progression. Further, our findings provide a neuropathological clue as to how endothelial tight junction pathology may contribute to Alzheimer s disease pathogenesis in both synergistic and additive manners to typical amyloid-β and tau pathologies.