Wasteosomes (corpora amylacea) as a hallmark of chronic glymphatic insufficiency

Abstract

In different organs and tissues, the lymphatic system serves as a drainage system for interstitial fluid and is useful for removing substances that would otherwise accumulate in the interstitium. In the brain, which lacks lymphatic circulation, the drainage and cleaning function is performed by the glymphatic system, called so for its dependence on glial cells and its similar function to that of the lymphatic system. In the present article, we define glymphatic insufficiency as the inability of the glymphatic system to properly perform the brain cleaning function. Furthermore, we propose that corpora amylacea or wasteosomes, which are protective structures that act as waste containers and accumulate waste products, are, in fact, a manifestation of chronic glymphatic insufficiency. Assuming this premise, we provide an explanation that coherently links the formation, distribution, structure, and function of these bodies in the human brain. Moreover, we open up new perspectives in the study of the glymphatic system since wasteosomes can provide information about which variables have the greatest impact on the glymphatic system and which diseases occur with chronic glymphatic insufficiency. For example, based on the presence of wasteosomes, it seems that aging, sleep disorders, and cerebrovascular pathologies have the highest impact on the glymphatic system, whereas neurodegenerative diseases have a more limited impact. Furthermore, as glymphatic insufficiency is a risk factor for neurodegenerative diseases, information provided by wasteosomes could help to define the strategies and actions that can prevent glymphatic disruptions, thus limiting the risk of developing neurodegenerative diseases.

Keywords: brain; corpora amylacea; glymphatic system; wasteosomes.

Fig. 1.

Brief description of the glymphatic system. (1) The glymphatic system involves the entry of CSF from the subarachnoid space into the periarterial spaces, its movement along these spaces propelled by the pulsatility of the arterial walls, and the displacement of water from the periarterial spaces to the brain parenchyma, where it mixes with brain ISF. (2) Fresh ISF flows across the brain parenchyma, moving along an anatomical pathway that is guided in some cases by the white matter tracts, and dragging away substances that would otherwise accumulate in the parenchyma. (3) Some of the ISF leaves the brain through the perivenous spaces (principally those of the large-caliber ventral veins and some superficial veins), most of it bypassing the CSF of the subarachnoid space. (4) ISF can also drain through the cranial and spinal nerves. (5) The subependymal and transependymal routes are additional pathways that ISF uses to exit the nervous system. As a result, the glymphatic system constitutes an important brain cleaning system. See text for details.

Fig. 2.

Hypothesized relationship between wasteosomes and the glymphatic system under chronic insufficiency. Aging (1), sleep disorders (2), and cardiovascular diseases (3) can exert a direct and chronic effect on the glymphatic system. In this case, waste elements are poorly removed and accumulate in the brain parenchyma, mainly in the drainage areas of the glymphatic system. Hence, wasteosomes are mainly formed in the regions near both the large-caliber ventral veins and some superficial veins, as well as the roots of the cranial and spinal nerves and the subependymal spaces. Neurodegenerative diseases (4) or an excessive production of waste substances in specific regions (5) can induce the local formation of wasteosomes. Due to the restricted flow of ISF, waste products can also accumulate in specific regions of the brain parenchyma like the bordering subpial spaces (6). By forming wasteosomes and incorporating waste materials into resistant polyglucosan structures formed of amylopectin-like polymers, astrocytes help in the removal and isolation of waste substances. Wasteosomes that are generated in the glia limitans or in proximity to CSF can be extruded by astrocytes into the CSF and subsequently be phagocytosed by M2 macrophages, thus leading to protective noninflammatory responses. Furthermore, wasteosomes located in the most internal regions remain in the astrocytes and, therefore, accumulate in the brain. Consequently, wasteosomes can be considered a hallmark of chronic glymphatic insufficiency. As can be seen, wasteosomes are mainly observed in perivenous, periventricular, and subpial spaces although they can also be present in some other regions. See text for details.