Harmsen, H. | Search bioRxiv

bioRxiv2024

Arteriolar degeneration and stiffness in cerebral amyloid angiopathy are linked to β-amyloid deposition and lysyl oxidase.

Cerebral amyloid angiopathy (CAA) is a vasculopathy characterized by vascular {beta}-amyloid (A{beta}) deposition on cerebral blood vessels. CAA is closely linked to Alzheimers disease (AD) and intracerebral hemorrhage. CAA is associated with the loss of autoregulation in the brain, vascular rupture, and cognitive decline. To assess morphological and molecular changes associated with the degeneration of penetrating arterioles in CAA, we analyzed post-mortem human brain tissue from 26 patients with mild, moderate, and severe CAA end neurological controls. The tissue was optically cleared for three-dimensional light sheet microscopy, and morphological features were quantified using surface volume rendering. We stained A{beta}, vascular smooth muscle (VSM), lysyl oxidase (LOX), and vascular markers to visualize the relationship between degenerative morphological features, including vascular dilation, dolichoectasia (variability in lumenal diameter) and tortuosity, and the volumes of VSM, A{beta}, and LOX in arterioles. Atomic force microscopy (AFM) was used to assess arteriolar wall stiffness, and we identified a pattern of morphological features associated with degenerating arterioles in the cortex. The volume of VSM associated with the arteriole was reduced by around 80% in arterioles with severe CAA and around 60% in cases with mild/moderate CAA. This loss of VSM correlated with increased arteriolar diameter and variability of diameter, suggesting VSM loss contributes to arteriolar laxity. These vascular morphological features correlated strongly with A{beta} deposits. At sites of microhemorrhage, A{beta} was consistently present, although the morphology of the deposits changed from the typical organized ring shape to sharply contoured shards with marked dilation of the vessel. AFM showed that arteriolar walls with CAA were more than 400% stiffer than those without CAA. Finally, we characterized the association of vascular degeneration with LOX, finding strong associations with VSM loss and vascular degeneration. These results show an association between vascular A{beta} deposition, microvascular degeneration, and increased vascular stiffness, likely due to the combined effects of replacement of VSM by {beta}-amyloid, cross-linking of extracellular matrices (ECM) by LOX, and possibly fibrosis. This advanced microscopic imaging study clarifies the association between A{beta} deposition and vascular fragility. Restoration of physiologic ECM properties in penetrating arteries may yield a novel therapeutic strategy for CAA.

neuroscience↗

bioRxiv2022

New insights into 4,000 years of resource economy across Greenland using ancient DNA

The success and failure of past cultures across the Arctic was tightly coupled to the ability of past people to exploit the full range of resources available to them, and to adapt to fluctuations in resource availability. There is substantial evidence for the hunting of birds, caribou and a wide range of marine mammals in pre-historic Greenland from bone remains preserved in ancient middens. However, the extent to which these communities relied on marine resources such as fish and large cetaceans is understudied because of the taphonomic processes and bias that affect how these taxa present themselves in the archaeological record. To address this, we analyse DNA from bulk bone samples from 12 archaeological sites across Greenland dating from Paleo-Inuit to Neo-Inuit periods. Using a combination of metabarcoding and shotgun metagenomics we identify an assemblage of 43 species consisting of birds, fish, and both marine and terrestrial mammals. We find genetic evidence of five different whale species, of which the bowhead whale (Balaena mysticetus) was the most commonly detected. Furthermore, we detect nine fish species, of which four have not previously been identified in any of the studied sites. Lastly, we identify a novel haplotype in caribou (Rangifer tarandus) at the 3,000-year-old site Itinnera, suggesting the presence of a distinct lineage of (now extinct) dwarfed caribou that colonised Greenland after the last ice age 9,000 years ago. Collectively, these findings provide a rare insight into whaling and fishing practices in Greenland and demonstrate that prehistoric Greenlandic communities had the social and technological capacity to target the largest whales available in the waters around them.

paleontology↗