Age‐associated changes in the blood‐brain barrier: comparative studies in human and mouse

Abstract

AimsWhile vascular pathology is a common feature of a range of neurodegenerative diseases, we hypothesized that vascular changes occur in association with normal ageing. Therefore, we aimed to characterize age‐associated changes in the blood–brain barrier (BBB) in human and mouse cohorts.MethodsImmunohistochemistry and Evans blue assays were used to characterize 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 prefrontal cortex (a total of 23 cases from 5 age groups representing the spectrum of young adult to old age: 20–30 years, 31–45 years, 46–60 years, 61–75 years and 75+) and C57BL/6 mice (3 months, 12 months, 18 months and 24 months, n = 5/6 per group).ResultsQuantification 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. Semiquantitative 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.ConclusionsThis study demonstrates BBB dysfunction in normal brain ageing, both in human and mouse cohorts.

The time course of recognition memory impairment and glial pathology in the hAPP-J20 mouse model of Alzheimer's disease.

“…This model exhibits both Aβ and NFTs allowing assessment of astrocyte response to both pathological features, and therefore may recapitulate aspects of AD more effectively than the J20 mouse model which only overexpresses levels of Aβ. A recent study by Goodall et al [67] reported an overall ageassociated increase in astrocyte activation in C57 mice, but in the current study this pattern was not observed and the lack of genotype-or age-associated proliferation may be partially attributable to astrocyte atrophy. Moreover, astrocyte atrophy can lead to synapse loss and reduced neuronal metabolic support, which can ultimately result in early cognitive deficits [66].…”

Age‐related ultrastructural changes of the basement membrane in the mouse blood‐brain barrier

“…A recent study demonstrated an increase in gliosis and GFAP expression associated with ageing in mice, but did not observe a change in the number or morphology of astrocytes. Astrocytes are the major source of lipoprotein constituents and lipoprotein assembly in the brain .…”

“…18 Some studies have found evidence that pericyte loss with ageing is associated with BBB breakdown in mice, but loss of pericyte coverage in the human brain capillaries was shown to have no correlation with age. 19 We can speculate that the loss of pericytes may stimulate BM synthesis by endothelial cells leading to an increase in the BM thickness with age.…”

White matter degeneration in vascular and other ageing‐related dementias

“…; Goodall et al . ). In contrast, loss of astrocytes and retraction of the end feet which express the transmembrane protein aquaporin 4 (AQP4) that forms channels selective for water mobility (Nagelhus and Ottersen ) were severely affected in the DWML (Chen et al .…”

“…Abnormalities in these proteins have been observed in a number of disorders associated with BBB dysfunction (Sandoval and Witt 2008;Weiss et al 2009). Quantification of these proteins to assess disruption of tight junctions and use as surrogate markers of BBB permeability indicated that these were not significantly affected in MRI defined DWML, although there was widespread albumin extravasation (Simpson et al 2010;Goodall et al 2017). In contrast, loss of astrocytes and retraction of the end feet which express the transmembrane protein aquaporin 4 (AQP4) that forms channels selective for water mobility (Nagelhus and Ottersen 2013) were severely affected in the DWML (Chen et al 2016).…”