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

Yu Yamazaki, Mitsuru Shinohara, Motoko Shinohara, Akari Yamazaki, Melissa E Murray, Amanda M. Liesinger, Michael G. Heckman, Elizabeth R. Lesser, Joseph E Parisi, Ronald Carl Petersen, Dennis W Dickson, Takahisa Kanekiyo, Guojun D Bu

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1077-1092
Number of pages16
JournalBrain : a journal of neurology
Volume142
Issue number4
DOIs
StatePublished - Apr 1 2019

Fingerprint

Tight Junction Proteins
Disease Progression
Alzheimer Disease
Amyloid
Brain
Claudin-5
Blood-Brain Barrier
Pathology
Occludin
Synaptophysin
Neurofibrillary Tangles
Tight Junctions
Neocortex
Proteins
Homeostasis
Endothelial Cells

Keywords

  • blood–brain barrier
  • claudin-5
  • neurovascular unit
  • occludin
  • tight junction

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Selective loss of cortical endothelial tight junction proteins during Alzheimer's disease progression. / Yamazaki, Yu; Shinohara, Mitsuru; Shinohara, Motoko; Yamazaki, Akari; Murray, Melissa E; Liesinger, Amanda M.; Heckman, Michael G.; Lesser, Elizabeth R.; Parisi, Joseph E; Petersen, Ronald Carl; Dickson, Dennis W; Kanekiyo, Takahisa; Bu, Guojun D.

In: Brain : a journal of neurology, Vol. 142, No. 4, 01.04.2019, p. 1077-1092.

Research output: Contribution to journalArticle

Yamazaki, Yu ; Shinohara, Mitsuru ; Shinohara, Motoko ; Yamazaki, Akari ; Murray, Melissa E ; Liesinger, Amanda M. ; Heckman, Michael G. ; Lesser, Elizabeth R. ; Parisi, Joseph E ; Petersen, Ronald Carl ; Dickson, Dennis W ; Kanekiyo, Takahisa ; Bu, Guojun D. / Selective loss of cortical endothelial tight junction proteins during Alzheimer's disease progression. In: Brain : a journal of neurology. 2019 ; Vol. 142, No. 4. pp. 1077-1092.
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