Sevao, M. | bioRxiv Science

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↗