Many neurodegenerative conditions are characterized by the aggregation of altered proteins, such amyloid-β, α-synuclein, tau, and others. Once altered they can form solid deposits with a halo of surrounding biochemistry that is toxic and disruptive to the normal function of cells in the brain. Why do these protein aggregates only become significant in later life? There is some pace at which they are created, and some pace at which they are cleared by various mechanisms. For example, amyloid-β is an antimicrobial peptide, a component of the innate immune system. More will be created in the brains of people suffering persistent viral infections, which may explain the much-debated link between herpesviruses and risk of Alzheimer's disease.
On the clearance side of the house, the immune cells of the brain are in part responsible for cleaning up protein aggregates. As the environment becomes more inflammatory, and other issues in aging impair immune function more generally, these cells falter in the task of removing aggregates. Of late, researchers have also directed their attention towards the physical clearance of aggregates from the brain via drainage of cerebrospinal fluid. The hypothesis on which Leucadia Therapeutics was founded is that Alzheimer's starts in the olfactory bulb because it is primarily drained through the cribriform plate, a path that is slowly closed off by ossification in later life. The glymphatic system provides drainage from the rest of the brain, and its function declines with age as well. To what degree can neurodegenerative conditions be postponed or reversed by restoring drainage, and thus a more youthful pace of removal of aggregates? The fastest way to answer that question is to try it and see.
Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases. Currently, no cure is available although epidemiological studies suggest that the risk of developing neurodegenerative diseases can be modulated by lifestyle-related factors, suggesting that some cases could be prevented. The toxic accumulation, misfolding, or mis-localisation of proteins leading to neuronal loss, i.e. proteinopathies, are key pathological features of age-related neurodegenerative diseases.
Breakdown or removal of the proteins which are susceptible to form toxic aggregates is essential to prevent development of pathology. Many of these proteins, such as AD associated amyloid-β and tau and PD associated α-synuclein, are found in the cerebrospinal fluid (CSF). This raised the question of the significance of CSF for clearing toxic metabolites from the brain, and in 2012, the glial-lymphatic ("glymphatic") system, that describes a mechanism for brain clearance via a perivascular (also referred to as paravascular) CSF flow pathway was characterised. Indeed, the glymphatic system plays a role in clearance of amyloid-β, tau, and α-synuclein.
The glymphatic brain clearance mechanism relies on interchange of CSF and interstitial fluid (ISF) that allows waste to be transferred to the CSF and transported out of the brain. The system was named the glia-lymphatic or "glymphatic" system upon its discovery in 2012 as astrocyte end feet are a main structural component of the fluid exchange pathway. CSF is predominantly produced in the choroid plexus in the 3rd and lateral ventricles, and it is circulated from the ventricles to the subarachnoid space surrounding the brain primarily by arterial pulsations. The subarachnoid space is continuous with the periarterial spaces of the pial vessels, from which the CSF enters the brain parenchyma, where it facilitates the clearance of solutes, although the efflux routes are less described.
The interchange of CSF and ISF is dependent on aquaporin 4 (AQP4) water channels on astrocyte endfeet that enwrap the cerebral vasculature. Changes in AQP4 expression or polarisation - referring to the differential distribution of AQP4 in the endfeet versus rest of the cell - are associated with disturbances in glymphatic function. In line with the observation that the glymphatic system can clear amyloid-β, decreased glymphatic function caused by deletion of the Aqp4 gene in an animal model of Alzheimer's disease leads to increased accumulation of amyloid-β and tau. Abnormalities in AQP4 polarisation are also seen in Alzheimer's patients, which provides some evidence that glymphatic function might also play a role in Alzheimer's disease in humans.