Biology subjects

Iliff, J.

Publications and source records attributed to Iliff, J..

6 recordsLinked to original sources

bioRxiv2026

Glymphatic function restored by α1-noradrenergic antagonism alleviates headache allodynia in mice

Mild traumatic brain injury (mTBI) often leads to migraine-like post-traumatic headache (PTH), yet effective treatments are limited. Clinical and preclinical studies have shown that mTBI disrupts glymphatic transport of cerebrospinal fluid in the brain. We hypothesized that altered glymphatic transport might underlie facial allodynia commonly associated with migraine and PTH. A closed-head impact model was used to induce mTBI in mice. Facial allodynia, a symptom of PTH and migraine, was evaluated using periorbital von Frey testing. Glymphatic influx was assessed using slice-based imaging of a fluorescent tracer injected into the cisterna magna. Here we show that prazosin (PZN), an 1-noradrenergic receptor antagonist, restores glymphatic function and treats facial allodynia induced by calcitonin gene-related peptide (CGRP) and a nitric oxide donor in mice. In contrast, propranolol, a {beta}-noradrenergic receptor antagonist, was ineffective. Even in the absence of mTBI, CGRP reduced glymphatic function and PZN was able to restore glymphatic function in the dorsal cortex. Importantly, the role of glymphatic function was confirmed by the lack of PZN efficacy in aquaporin-4 knockout mice. These findings indicate that targeting 1-noradrenergic receptors to enhance glymphatic transport may offer a therapeutic strategy for treating migraine and PTH.

neuroscience↗

bioRxiv2024

Aquaporin-4 mis-localization slows glymphatic clearance of α-synuclein and promotes α-synuclein pathology and aggregate propagation

The appearance of misfolded and aggregated proteins is a pathological hallmark of numerous neurodegenerative diseases including Alzheimers disease and Parkinsons disease. Sleep disruption is proposed to contribute to these pathological processes and is a common early feature among neurodegenerative disorders. Synucleinopathies are a subclass of neurodegenerative conditions defined by the presence of -synuclein aggregates, which may not only enhance cell death, but also contribute to disease progression by seeding the formation of additional aggregates in neighboring cells. The mechanisms driving intercellular transmission of aggregates remains unclear. We propose that disruption of sleep-active glymphatic function, caused by loss of precise perivascular AQP4 localization, inhibits -synuclein clearance and facilitates -synuclein propagation and seeding. We examined human post-mortem frontal cortex and found that neocortical -synuclein pathology was associated with AQP4 mis-localization throughout the gray matter. Using a transgenic mouse model lacking the adapter protein -syntrophin, we observed that loss of perivascular AQP4 localization impairs the glymphatic clearance of -synuclein from intersititial to cerebrospinal fluid. Using a mouse model of -synuclein propogation, using pre-formed fibril injection, we observed that loss of perivascular AQP4 localization increased -synuclein aggregates. Our results indicate -synuclein clearance and propagation are mediated by glymphatic function and that AQP4 mis-localization observed in the presence of human synucleinopathy may contribute to the development and propagation of Lewy body pathology in conditions such as Lewy Body Dementia and Parkinsons disease. SummaryIn a human postmortem case series, we observe that neocortical Lewy body pathology is associated with mis-localization of the astroglial water channel aquaporin-4 (AQP4). In mice, -synuclein is cleared from the brain along perivascular pathways, while loss of perivascular AQP4 localization impairs glymphatic -synuclein clearance to the CSF. Furthermore, loss of perivascular AQP4 localization promotes the development and propagation of -synuclein aggregates.

neuroscience↗

bioRxiv2024

Biological sex and BMI influence the longitudinal evolution of adolescent and young adult MRI-visible perivascular spaces

Background and PurposeAn association recently emerged between magnetic resonance imaging (MRI)-visible perivascular spaces (MV-PVS) with intracerebral solute clearance and neuroinflammation, in adults. However, it is unknown how MV-PVS change throughout adolescence and what factors influence MV-PVS volume and morphology. This study assesses the temporal evolution of MV-PVS volume in adolescents and young adults, and secondarily evaluates the relationship between MV-PVS, age, sex, and body mass index (BMI). Materials and MethodsThis analysis included a 783 participant cohort from the longitudinal multicenter National Consortium on Alcohol and Neurodevelopment in Adolescence study that involved up to 6 imaging visits spanning 5 years. Healthy adolescents aged 12-21 years at study entry with at least two MRI scans were included. The primary outcome was mean MV-PVS volume (mm3/white matter cm3). ResultsOn average, males had greater MV-PVS volume at all ages compared to females. A linear mixed-effect model for MV-PVS volume was performed. Mean BMI and increases in a persons BMI were associated with increases in MV-PVS volume over time. In females only, changes in BMI correlated with MV-PVS volume. One unit increase in BMI above a persons average BMI was associated with a 0.021 mm3/cm3 increase in MV-PVS volume (p<0.001). ConclusionThis longitudinal study showed sex differences in MV-PVS features during adolescence and young adulthood. Importantly, we report that increases in BMI from a persons mean BMI are associated with increases in MV-PVS volume in females only. These findings suggest a potential link between MV-PVS, sex, and BMI that warrants future study.

neuroscience↗

bioRxiv2024

The Impact of Anesthesia on Ultrasonic Glymphatic Perturbation Protocol: Alertness, and Glymphatic Influx

We have recently discovered that transcranial low-intensity focused ultrasound can enhance glymphatic transport, which facilitates the removal of waste metabolites from the brain in a preclinical rat model [1]. The central hypothesis was that ultrasound, functioning as a pressure wave, has the potential to influence the convective forces generated by arterial pulsations, which are also pressure waves, serving as the primary mechanism for glymphatic transport. Importantly, our data revealed that (i) the ultrasound protocol (650 kHz at 0.2MPa for 10 minutes to the entire brain) is safe, as histological evaluations showed no parenchymal damage and no difference in levels of neuronal degeneration or astrocytic activation 72 hours after the intervention, and (ii) the required pressure is significantly low, 10 times below FDA-approved limits for diagnostic ultrasound, and can be achieved using existing FDA-approved clinical transcranial focused ultrasound systems, suggesting its ease of translation into clinical applications. However, the study was conducted under specific physiological states with approximately 2.5% isoflurane-induced anesthesia. There is a limitation in fully understanding the potential bioeffects of ultrasound within the glymphatic space across various physiological conditions, primarily because the glymphatic transports efficiency fluctuates with anesthetically induced physiological states. Hence, establishing standardized protocols of ultrasonic glymphatic transport at optimal physiological state is crucial for ensuring consistent, reliable results across research laboratories during the preclinical development of this technique. The primary objective of this study is to evaluate how ultrasonically manipulated glymphatic transport is influenced by different levels of isoflurane-induced anesthetic conditions, including 3% (just above 2.5%), 2% (slightly below 2.5%), and 1.5% (quasi-awake state, resembling the existing clinical practice of ultrasound treatment). Results show that the impact of ultrasound during glymphatic transport depends on the level of anesthesia. It increases alertness in lightly anesthetized animals and improves glymphatic transport, while it induces drowsiness in heavily anesthetized animals, leading to reduced glymphatic transport. The results suggest that lighter anesthesia is beneficial for efficient ultrasonic glymphatic transport, making it more in line with the awake state in current clinical ultrasound treatments, thus advancing the technology closer to clinical translation.

bioengineering↗

bioRxiv2023

Neuronal Ndst1 depletion accelerates prion protein clearance and slows neurodegeneration in prion infection

Select prion diseases are characterized by widespread cerebral plaque-like deposits of amyloid fibrils enriched in heparan sulfate (HS), a major extracellular matrix component. HS facilitates fibril formation in vitro, yet how HS impacts fibrillar plaque growth within the brain is unclear. Here we found that prion-bound HS chains are highly sulfated, and that the sulfation is essential for HS accelerating prion conversion in vitro. Using conditional knockout mice to deplete the HS sulfation enzyme, Ndst1 (N-deacetylase, N-sulfotransferase), from neurons or astrocytes, we investigated how reducing HS sulfation impacts survival and prion aggregate distribution during a prion infection. Neuronal Ndst1-depleted mice survived longer and showed fewer and smaller parenchymal plaques, shorter fibrils, and increased vascular amyloid, consistent with enhanced aggregate transit toward perivascular drainage channels. The prolonged survival was strain-dependent, affecting mice infected with extracellular, plaque-forming, but not membrane bound, prion strains. Live PET imaging revealed rapid clearance of prion protein monomers into the CSF in mice expressing unsulfated HS, further suggesting that HS sulfate groups hinder transit of extracellular prion monomers. Our results directly show how a host cofactor slows the spread of prion protein through the extracellular space and identify an enzyme target to facilitate aggregate clearance. Author summaryPrions cause a rapidly progressive neurologic disease and death with no curative treatment available. Prion aggregates accumulate exponentially in the brain in affected individuals triggering neuronal loss and neuroinflammation. Yet the additional molecules that facilitate aggregation are largely unknown, and their identification may lead to new therapeutic targets. We have found that prions in the brain preferentially bind to a highly sulfated endogenous polysaccharide, known as heparan sulfate (HS). Here we use genetically modified mice that express poorly sulfated neuron-derived HS, and infect mice with different prions strains. We find that the mice infected with a plaque-forming prion strain show a prolonged survival and fewer plaques compared to the controls. We also found that the prion protein was efficiently transported in the interstitial fluid in mice having poorly sulfated HS, suggesting that the prion protein is more readily cleared from the brain. Our study provides insight into how HS retains prion aggregates in the brain to accelerate disease and indicates the specific HS biosynthetic enzymes to target for enhancing protein clearance.

pathology↗

bioRxiv2021

MRI-Visible Perivascular Space (PVS) Changes with Long-Duration Spaceflight

Humans are exposed to extreme environmental stressors during spaceflight and return with alterations in brain structure and shifts in intracranial fluids. To date, no studies have evaluated the effects of spaceflight on perivascular spaces (PVSs) within the brain, which are believed to facilitate fluid drainage and brain homeostasis. Here, we examined how the number and morphology of magnetic resonance imaging (MRI)-visible PVSs are affected by spaceflight, including prior spaceflight experience. Fifteen astronauts underwent six T1-weighted 3T MRI scans, twice prior to launch and four times following their return to Earth after [~]6-month missions to the International Space Station. White matter MRI-visible PVS number and morphology were calculated using an established automated segmentation algorithm. We found that novice astronauts showed an increase in total PVS volume from pre- to post-flight, whereas experienced crewmembers did not (adjusted for age, sex, and time between landing and first MRI scan). Moreover, experienced astronauts exhibited a significant correlation between more previous flight days and greater PVS median length at baseline, suggesting that experienced astronauts exhibit holdover effects from prior spaceflight(s). There was also a significant positive correlation between pre- to post-flight increases in PVS median length and increases in right lateral ventricular volume. The presence of spaceflight associated neuro-ocular syndrome (SANS) was not associated with PVS number or morphology. Together, these findings demonstrate that spaceflight is associated with PVS morphological changes, and specifically that spaceflight experience is an important factor in determining PVS characteristics.

neuroscience↗