ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 Astrocytes

The accumulation of amyloid-β (Aβ) in the walls of capillaries and arteries as cerebral amyloid angiopathy (CAA) is part of the small vessel disease spectrum, related to a failure of elimination of Aβ from the brain. Aβ is eliminated along basement membranes in walls of cerebral capillaries and arteries (Intramural Peri-Arterial Drainage—IPAD), a pathway that fails with age and ApolipoproteinEε4 (ApoE4) genotype. IPAD is along basement membranes formed by capillary endothelial cells and surrounding astrocytes. Here, we examine (1) the composition of basement membranes synthesised by ApoE4 astrocytes; (2) structural differences between ApoE4 and ApoE3 astrocytes, and (3) how flow of Aβ affects Apo3/4 astrocytes. Using cultured astrocytes expressing ApoE3 or ApoE4, immunofluorescence, confocal, correlative light and electron microscopy (CLEM), and a millifluidic flow system, we show that ApoE4 astrocytes synthesise more fibronectin, possess smaller processes, and become rarefied when Aβ flows over them, as compared to ApoE3 astrocytes. Our results suggest that basement membranes synthesised by ApoE4 astrocytes favour the aggregation of Aβ, its reduced clearance via IPAD, thus promoting cerebral amyloid angiopathy.

The Pattern of AQP4 Expression in the Ageing Human Brain and in Cerebral Amyloid Angiopathy

In the absence of lymphatics, fluid and solutes such as amyloid-β (Aβ) are eliminated from the brain along basement membranes in the walls of cerebral capillaries and arteries—the Intramural Peri-Arterial Drainage (IPAD) pathway. IPAD fails with age and insoluble Aβ is deposited as plaques in the brain and in IPAD pathways as cerebral amyloid angiopathy (CAA); fluid accumulates in the white matter as reflected by hyperintensities (WMH) on MRI. Within the brain, fluid uptake by astrocytes is regulated by aquaporin 4 (AQP4). We test the hypothesis that expression of astrocytic AQP4 increases in grey matter and decreases in white matter with onset of CAA. AQP4 expression was quantitated by immunocytochemistry and confocal microscopy in post-mortem occipital grey and white matter from young and old non-demented human brains, in CAA and in WMH. Results: AQP4 expression tended to increase with normal ageing but AQP4 expression in severe CAA was significantly reduced when compared to moderate CAA (p = 0.018). AQP4 expression tended to decline in the white matter with CAA and WMH, both of which are associated with impaired IPAD. Adjusting the level of AQP4 activity may be a valid therapeutic target for restoring homoeostasis in the brain as IPAD fails with age and CAA.

Three poems on flood histories in rural Ireland

This article presents three poems inspired by archival research on historical perceptions of flooding and river engineering in Galway city and its rural hinterland. Relationships between people and water, as recorded in early-20th-century minutes of a vice-regal commission on river drainage in rural Ireland and historical newspaper accounts of flooding, are explored and reimagined. The poems focus particularly on the management of flood risk and geomorphological processes (erosion and sedimentation), ‘arterial drainage,’ and individual emotional responses to traumatic floods and their impacts. Reflecting on these poems, I suggest that part of poetry’s contribution to the discipline is to provide a new and exciting way of engaging with the archive.

Attribution of detected changes in streamflow using multiple working hypotheses

This paper revisits a widely cited study of the Boyne catchment in east Ireland that attributed greater streamflow from the mid-1970s to increased precipitation linked to a shift in the North Atlantic Oscillation. Using the method of multiple working hypotheses we explore a wider set of potential drivers of hydrological change. Rainfall–runoff models are used to reconstruct streamflow to isolate the effect of climate, taking account of both model structure and parameter uncertainty. The Mann–Kendall test for monotonic trend and Pettitt change point test are applied to explore signatures of change. Contrary to earlier work, arterial drainage and simultaneous onset of field drainage in the 1970s and early 1980s are now invoked as the predominant drivers of change in annual mean and high flows within the Boyne. However, a change in precipitation regime is also present in March, thereby amplifying the effect of drainage. This new explanation posits that multiple drivers acting simultaneously were responsible for the observed change, with the relative contribution of each driver dependant on the timescale investigated. This work demonstrates that valuable insights can be gained from a systematic application of the method of multiple working hypotheses in an effort to move towards more rigorous attribution, which is an important part of managing emerging impacts on hydrological systems.

Attribution of detected changes in streamflow using multiple working hypotheses

This paper revisits a widely cited study of the Boyne catchment in the east of Ireland that attributed a change in streamflow during the mid-1970s to increased precipitation linked to a shift in the North Atlantic Oscillation. Using the method of Multiple Working Hypotheses we explore a wider set of potential drivers of hydrological change. Rainfall-runoff models are employed to reconstruct streamflow to isolate the effect of climate taking account of both model structure and parameter uncertainty. The Mann–Kendall test for monotonic trend and Pettitt change point test are applied to explore signatures of change. Different to earlier work, arterial drainage and the simultaneous onset of field drainage in the 1970s and early 1980s were inferred to be the predominant driver of change within the Boyne. There is evidence that a change in precipitation regime is also present, albeit to a lesser extent. This new explanation posits that multiple drivers acting simultaneously were responsible for the observed change. This work highlights the utility of the Multiple Working Hypotheses framework in moving towards more rigorous attribution, which is an important part of managing unfolding impacts on hydrological systems.