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Replies to post #273476 on Anavex Life Sciences Corp (AVXL)
10/03/20 1:14 AM
The glymphatic and lymphatic systems
A fundamental tenet of brain homeostasis is that protein clearance must approximate protein synthesis. Is removal of protein waste also controlled by the sleep-wake cycle? Until 2012 it was believed that the brain, singular among organs, was recycling all of its own protein waste (21). Only a small number of proteins were known to be transported across the blood-brain barrier, and these did not include most of the primary proteins made or shed by brain cells (22). In the absence of lymphatic vessels or any overt pathways for fluid export, it was unclear how protein waste might exit the mature brain parenchyma. The default conclusion was that the classical cellular protein degradation pathways—autophagy and ubiquitination—must be responsible for all central nervous system (CNS) protein recycling (23).
This supposition, that the brain must recycle its own waste, was questioned after the discovery of the glymphatic system (24). The glymphatic system is a highly organized cerebrospinal fluid (CSF) transport system that shares several key functions, including the export of excess interstitial fluid and proteins, with the lymphatic vessels of peripheral tissues (Fig. 1A). Indeed, both the brain’s CSF and peripheral lymph are drained together into the venous system, from which protein waste is removed and recycled by the liver (25). Yet brain tissue itself lacks histologically distinct lymphatic vessels. Rather, fluid clearance from the brain proceeds via the glymphatic pathway, a structurally distinct system of fluid transport that uses the perivascular spaces created by the vascular endfeet of astrocytes (26). The endfeet surround arteries, capillaries, and veins, serving as a second wall that covers the entire cerebral vascular bed. The perivascular spaces are open, fluid-filled tunnels that offer little resistance to flow. This is in sharp contrast to the disorientingly crowded and compact architecture of adult brain tissue, the neuropil, through which interstitial fluid flow is necessarily slow and restricted—akin to a marsh, flowing to the glymphatic system’s creeks and then rivers (27). The glymphatic system’s perivascular tunnels are directly connected to the subarachnoid spaces surrounding the brain, from which CSF is rapidly driven into deep regions of the brain by the cardiac rhythm–linked pulsations of the arterial wall (28). The vascular endfeet of astrocytes, a primary subtype of glial cells, surround the perivascular spaces and can be regarded as open gates for fluid influx into the neuropil. The astrocytic endfeet are connected by gap junctions, and almost 50% of their plasma membrane facing the vessel wall is occupied by square arrays composed of the water channel protein aquaporin-4 (AQP4) (29). Deletion of AQP4 channels in mice reduces both the influx of CSF tracers and the efflux of solutes from the neuropil (24, 30, 31). Given this pathway’s functional similarities to the peripheral lymphatic system, we termed this astrocyte-regulated mechanism of brain fluid transport the “glymphatic (glial-lymphatic) system.”
Autophagy happens while we're sleeping
It's just as important for our cells to clean themselves out and clear away debris. It's a process most of us don't think about—and haven't even heard of—called autophagy (which means self-eating).
New preclinical data establishes ANAVEX®2-73 as a modulator of autophagy through Sigma-1 receptor activation, possibly needed for the prevention and treatment of neurodegenerative conditions including Alzheimer’s disease, Parkinson’s disease and ALS
The current findings show for the first time that activation of Sig-1R with ANAVEX®2-73 leads to the prominent induction of the autophagy “cellular recycling” process and enhanced protein clearance in cells. The study, led by Christian Behl et. al. of the University Medical Center at Johannes Gutenberg University, in Mainz, Germany, has been published in the peer-reviewed journal, Cells
