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.