Age-related neurodegeneration is characterized by rising levels of various protein aggregates in the brain. A few of the many thousands of proteins in the body can become misfolded in ways that encourage other molecules of the same protein to also misfold in the same way, forming structures that spread and precipitate into solid deposits. These aggregates are accompanied by a halo of surrounding biochemistry that is toxic to neurons, disrupting function in the brain and killing vital cells, causing loss of cognitive function and ultimately death.
In recent years, increasing attention has been given to the role of cerebrospinal fluid drainage in maintaining the brain. The circulation of cerebrospinal fluid is not a closed system, but one that drains into the body via a few different routes. This is a path for molecular waste of all sorts to be removed from brain tissue, but unfortunately it deteriorates with age. The company Leucadia Therapeutics is founded on evidence for one such drainage path, through the cribriform plate, to become blocked with age, thereby leading to the early stages of Alzheimer's disease because amyloid-β cannot be cleared as rapidly as is needed. Similarly, other paths through the glymphatic system also deteriorate with age, for different reasons, and with similar consequences for the clearance of molecular waste.
Today's open access paper is of interest in this broader context. It examines one of the mechanisms by which waste can be packaged up into granules, exported from brain tissue into the cerebrospinal fluid, and thereby drained from the brain to be dealt with by immune cells elsewhere in the body.
In 1837 the anatomist and physiologist J. E. Purkinje described the presence of some particular granular bodies in the brain of elderly patients. These bodies, named corpora amylacea (CA), were initially considered to have no pathological significance and for a long time were thought to be irrelevant. In recent decades, however, this perception has changed. With the advances in technology, CA have been studied from different perspectives and a large number of theories regarding their nature have been put forward. Unfortunately, none of these theories have been demonstrated conclusively and CA remain intriguing and mysterious bodies. In the present study, several features of CA are described and a vision of their function is proposed which may have implications for clinical practice.
There is a consensus that the main components of CA are polymerized hexoses (primarily glucose). Other components originating in neurons, astrocytes, or oligodendrocytes, from blood or of fungal or viral origin, have also been described. We observed that CA contain glycogen synthase (GS), an indispensable enzyme for polyglucosan formation, and also ubiquitin and protein p62, both associated with processes of elimination of waste substances. The relationship between CA and waste substances is recurrent in the literature. CA functions seem to be directed towards trapping and sequestration of potentially hazardous products of cellular metabolism, principally derived from the aging process, but probably also from any disease state resulting in excessive amounts of potentially harmful metabolic products.
It is well known that CA are located mainly in perivascular, periventricular, and subpial regions of the brain. Since the glymphatic system drains the interstitial fluid (ISF) from the perivascular regions to the cerebrospinal fluid (CSF), and since both periventricular and subpial regions are close to the cavities that contain the CSF (i.e., ventricles and subarachnoid space), it is plausible that CA are expelled from the brain to the CSF. The CSF drains not only via arachnoid granulations, as classically believed, but also via the recently rediscovered meningeal lymphatic system. From meningeal lymphatic vessels and subsequent lymphatic vessels, lymph crosses different cervical lymph nodes before accessing the lymphatic duct or right thoracic duct, which ultimately drain into the brachiocephalic veins.
On this basis, it has been reported that meningeal lymphatic vessels allow the brain to eliminate macromolecules by collecting them from the CSF. Conceivably, in the same way as waste molecules generated in the brain, it is possible that CA released from the brain into the CSF escape from the CSF via the meningeal lymphatic system, reaching the deep cervical lymph nodes or beyond. The lymphatic capillaries are formed by overlapping cells that can act as valves leaving relatively large openings, allowing the passage of macromolecules and even cells, and thus also the passage of CA. Overall, this evidence suggests a mechanism for eliminating residual substances from the brain in which CA act as waste containers that are extruded from the brain to the CSF. Afterward, via the meningeal lymphatic system, CA can reach the cervical lymph nodes, and macrophages located there may play a significant role in their phagocytosis.
This study shows that CA are released from periventricular and subpial regions to the cerebrospinal fluid and are present in the cervical lymph nodes, into which cerebrospinal fluid drains through the meningeal lymphatic system. We also show that CA can be phagocytosed by macrophages. We conclude that CA can act as containers that remove waste products from the brain and may be involved in a mechanism that cleans the brain. Moreover, we postulate that CA may contribute in some autoimmune brain diseases, exporting brain substances that interact with the immune system, and hypothesize that CA may contain brain markers that may aid in the diagnosis of certain brain diseases.