Biology subjects

Harrison, I. F.

Publications and source records attributed to Harrison, I. F..

3 recordsLinked to original sources

bioRxiv2024

Evidence for reduced choroid plexus volume in the aged brain

BackgroundThe choroid plexus plays an important role in brain homeostasis, including the active secretion of cerebrospinal fluid. Its function and structure have been reported to be affected by normal ageing. However, existing measures of choroid plexus volume may be complicated by partial volume (in vivo MRI) and tissue fixation artefacts (histology). In this study, we investigate possible changes in choroid plexus volume within the lateral ventricles of aged mice utilising two structural MRI protocols explicitly designed for time-efficient, high-resolution in vivo imaging of the choroid plexus. MethodsTwo MRI sequences were utilised to examine in vivo choroid plexus volume in the lateral ventricles of young ([~]6 months) and aged ([~]24 months) mouse brains: 1) an ultra-long echo-time T2 weighted fast-spin-echo and 2) a multi-TE T2* mapping protocol. A test-retest study was performed on a subset of the data to examine the reproducibility of choroid plexus volume estimation. A two-way ANOVA test was performed to determine possible differences in choroid plexus volume in young and aged mouse groups across the two distinct MRI protocols. ResultsReproducibility tests showed a low test-retest variability of the manual segmentation pipeline for both MRI protocols. A statistically significant reduction of in vivo choroid plexus volume was found in the aged mouse brain. This finding is concordant with previous histology studies that have observed a reduction in epithelial cell height with ageing across a wide range of species. ConclusionsWe present an in vivo investigation of changes to lateral ventricle choroid plexus volume in the mouse brain utilising a manual segmentation approach based on two bespoke MRI protocols designed for time-efficient high resolution imaging of the choroid plexus. Furthermore, based on these protocols, we provide evidence for a reduction in choroid plexus volume in the aged brain. This research provides insight for studies utilising MRI measurements of choroid plexus volume as a biomarker of age-related neurologic conditions as it indicates that the ageing process itself does not result in hypertrophy of the choroid plexus, but a decrease in tissue volume.

neuroscience↗

bioRxiv2024

Influence of the Glymphatic System on α-Synuclein Propagation: Role of Aquaporin-4 and the Dystrophin-Associated Protein Complex

Propagation and aggregation of prion proteins, such as tau and -synuclein (Syn), are key pathological features of neurodegenerative diseases. Extracellular clearance pathways, such as the glymphatic system, may play a crucial role in the removal of these toxic proteins from the brain. Primarily active during sleep, this system relies on aquaporin-4 (AQP4) water channel expression and polarisation to astrocytic endfeet, facilitating interstitial solute clearance. Glymphatic dysfunction has recently been implicated in Parkinsons disease, however the precise mechanisms underlying the pathogenic effect of this dysfunction remain unclear. This includes how impaired glymphatic function influences Syn propagation dynamics, and the role of propagating Syn itself on glymphatic function. In this study, we used a mouse model of Syn propagation to elucidate the impact of Syn aggregation on glymphatic function, by measuring CSF-ISF exchange and assessing AQP4 and associated endfoot complex proteins in the brain over time and across different regions. Our results show that direct injection of Syn pre-formed fibrils leads to reduced expression of the AQP4 endfoot complex, but propagation of endogenous Syn induces an enhancement of glymphatic function suggesting compensatory upregulation in response to increasing endogenous Syn load. To determine the influence of glymphatic dysfunction on Syn propagation dynamics, we then employed a pharmacological approach to inhibit glymphatic function in this model. Acute glymphatic inhibition significantly reduced brain to CSF Syn clearance, and chronic treatment exacerbated Syn pathology, neurodegeneration, and motor behavioural deficits in mice. Together our findings show that Syn clearance and propagation are modulated by glymphatic function and suggest that AQP4 complex dysregulation may contribute to glymphatic impairment associated with Parkinsons diseases. Summary for the non-scientific communityThe glymphatic system clears brain waste during sleep. Lopes et al. show that -synuclein, a protein linked to Parkinsons, is cleared by this system. Using a mouse model of the disease, they suggest that aquaporin-4 water channels may impair glymphatic function, contributing to -synuclein buildup in patients brains.

neuroscience↗

bioRxiv2023

Glymphatic Inhibition Exacerbates Tau Propagation in an Alzheimers Disease Model

BackgroundThe aggregation and spread of misfolded amyloid structured proteins, such as tau and -synuclein, are key pathological features associated with neurodegenerative disorders, including Alzheimers and Parkinsons disease. These proteins possess a prion-like property, enabling their transmission from cell to cell leading to propagation throughout the central and peripheral nervous systems. While the mechanisms underlying their intracellular spread are still being elucidated, targeting the extracellular space has emerged as a potential therapeutic approach. The glymphatic system, a brain-wide pathway responsible for clearing extracellular metabolic waste from the central nervous system, has gained attention as a promising target for removing these toxic proteins. MethodsIn this study, we investigated the impact of long-term modulation of glymphatic function on tau aggregation and spread by chronically treating a mouse model of tau propagation with a pharmacological inhibitor of AQP4, TGN-020. Thy1-hTau.P301S mice were intracerebrally inoculated with tau into the hippocampus and overlying cortex, and subsequently treated with TGN-020 (3 doses/week, 50mg/kg TGN-020, i.p.) for 10-weeks. During this time, animal memory was studied using cognitive behavioural tasks, and structural MR images were acquired of the brain in vivo prior to brain extraction for immunohistochemical characterisation. ResultsOur findings demonstrate increased tau aggregation in the brain and transhemispheric propagation in the hippocampus and cortex following the inhibition of glymphatic clearance. Moreover, disruption of the glymphatic system aggravated recognition memory in tau inoculated mice and exacerbated regional changes in brain volume detected in the model. When initiation of drug treatment was delayed for several weeks post-inoculation, the aforementioned alterations were attenuated. ConclusionsThese results indicate that by modulating AQP4 function and, consequently, glymphatic clearance, it is possible to modify the propagation and pathological impact of tau in the brain, particularly during the initial stages of the disease. These findings highlight the critical role of the glymphatic system in preserving healthy brain homeostasis and offer valuable insights into the therapeutic implications of targeting this system for managing neurodegenerative diseases characterized by protein aggregation and spread.

neuroscience↗