Age-associated changes in the blood brain barrier: Comparative studies in human and mouse

Goodall, Emily F.; Wang, Chunfang; Simpson, Julie E.; Baker, David J.; Drew, David R.; Heath, Paul R.; Saffrey, M. Jill; Romero, Ignacio A. and Wharton, Stephen B. (2018). Age-associated changes in the blood brain barrier: Comparative studies in human and mouse. Neuropathology and Applied Neurobiology, 44(3) pp. 328–340.



Aims: While vascular pathology is a common feature of a range of neurodegenerative diseases, we hypothesised that vascular changes occur in association with normal ageing. Therefore we aimed to characterise age-associated changes in the blood brain barrier (BBB) in human and mouse cohorts.

Methods: Immunohistochemistry and Evans Blue assays were used to characterise BBB dysfunction (tight junction protein expression and serum plasma protein accumulation), vascular pathology (pericyte loss and vascular density) and glial pathology (astrocyte and microglial density) in ageing neurological control human pre-frontal cortex (a total of 23 cases from 5 age groups representing the spectrum of young adult to old age: 20-30yrs, 31-45yrs, 46-60yrs, 61-75yrs and 75+) and C57BL/6 mice (3 month, 12 month, 18 month and 24 month, n=5/6 per group).

Results: Quantification of the tight junction protein ZO-1 within the cortex and cerebellum of the mouse cohort showed a significant trend to both increased number (cortex p<0.001, cerebellum p<0.001) and length (cortex p<0.001, cerebellum p<0.001) of junctional breaks associated with increasing age. GFAP expression significantly correlated with ageing in the mice (p=0.037). In the human cohort assessment of human protein accumulation (albumin, fibrinogen and human IgG) demonstrated cells morphologically resembling clasmatodendritic astrocytes, indicative of BBB dysfunction. Semi-quantitative assessment of astrogliosis in the cortex expression revealed an association with age (p=0.003), while no age-associated changes in microglial pathology, microvascular density or pericyte coverage were detected.

Conclusions: This study demonstrates BBB dysfunction in normal brain ageing, both in human and mouse cohorts.

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