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

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

Uncovering tau in wasteosomes (corpora amylacea) of Alzheimer's disease patients

Brain corpora amylacea, recently renamed as wasteosomes, are polyglucosan bodies that appear during aging and some neurodegenerative conditions. They collect waste substances and are part of a brain cleaning mechanism. For decades, studies on their composition have produced inconsistent results and the presence of tau protein in them has been controversial. In this work, we reanalyzed the presence of this protein in wasteosomes and we pointed out a methodological problem when immunolabeling. It is well known that to detect tau it is necessary to perform an antigen retrieval. However, in the case of wasteosomes, an excessive antigen retrieval with boiling dissolves their polyglucosan structure, releases the entrapped proteins and, thus, prevents their detection. After performing an adequate pre-treatment, with an intermediate time of boiling, we observed that some brain wasteosomes from patients with Alzheimer's disease (AD) contained tau, while we did not detect tau protein in those from non-AD patients. These observations pointed the different composition of wasteosomes depending on the neuropathological condition and reinforce the role of wasteosomes as waste containers

Face-to-face teaching: the opinion and the commitment of the students of Physiology and Pathophysiogy III in the Pharmacy Degree of the University of Barcelona

Although university teachers and students made a significant effort to adapt to a virtual scenario during the pandemic, face-to-face teaching is considered the priority system at the University of Barcelona. However, after the pandemic period, the presence of the students in the classroom has been clearly reduced. The teachers of the subject of Physiology and Pathophysiology III of the Pharmacy Degree of the University of Barcelona have designed a survey to capture the degree of satisfaction of the students about the development of face-to-face teaching tuition and to investigate their commitment to attend the classes in the classroom. The students answered this survey on the day of the final exam. The number of students in the course 2022-2023 is 313 and 95 % of them (296 students) answered the survey, which was voluntary and anonymous. In the analysis of the results obtained, we have differentiated between the students who coursed the subject for the first time (242 students) and those who failed in previous academic years and enrolled for the second or the third time (46 students). Results indicated that the students valued positively face-to-face teaching, as 94% of all the students who answered the poll rated "quiet" or "a lot" this tuition. If we consider only the students who matriculated the subject for the first time, the degree of satisfaction increased to 95% while it decreased to 90% when the students that already coursed the subject before were assessed. When they were asked about their commitment to assist the lessons at the classroom, with the question "How often have you attended the face-to-face classes?", 77% of the students answered "quite" or "a lot". Again, if we consider the students who coursed the subject for the first time, this value increased to 81% and decreased to 61% for those who were matriculated in the subject after failing it the previous year. The main reasons that they argued for not assisting to the classes were mainly 1) lack of time due to other continuous assessment exams and activities and 2) working hours. Only 1.7% of the students adduced their absence from the classroom to reasons related to the teaching quality. In conclusion, the students are in line with our university's face-to-face teaching methods, as they continue to positively value classroom teaching, despite having lived through the pandemics, when they took online classes. Their responses to the survey show us that students of the Pharmacy Degree may feel overwhelmed with the activities and exams scheduled during each term, the lack of time the reason for not attending regular face-to-face classes every day

From corpora amylacea to wasteosomes

[eng] Corpora amylacea (CA) in the human brain are polyglucosan aggregates that were first described by J.E. Purkinje in 1837. They are intracellular astrocytic bodies that accumulate mainly in perivascular, periventricular and subpial regions of the aging brain, but are also present in large numbers in specific areas of the brain in neurodegenerative conditions. Different studies suggest that the function of CA seems to be directed towards trapping products derived from aging or degenerative processes. While essentially constituted of polymerized hexoses, primarily glucose, a wide range of components have been described in CA, some of them derived from neurons, astrocytes, oligodendrocytes or blood, or even related to viral, fungal or microbial infections. Their location in the perivascular, periventricular and subpial regions of the brain, all of them connected or close to cavities filled with cerebrospinal fluid (CSF), suggests that CA can be extruded from these regions into the CSF. Furthermore, CA contain neo-epitopes (NE) of an unknown nature that are recognized by natural antibodies of IgM type. This IgM-NE interaction indicates that if CA were released from the central nervous system (CNS), they could interact with the natural immune system, which could intervene in their elimination. This body of evidence allowed us to consider that CA not only entrap residual products, but also act as waste containers involved in a cleaning mechanism that removes residual substances from the CNS. Accordingly, this thesis aimed to verify this hypothesis. Our studies revealed the presence of CA in the CSF and in the cervical lymph nodes, into which CSF drains through the meningeal lymphatic system. In the cervical lymph nodes, we observed CA making contact with certain cells that, according to their location, shape, and staining properties may be macrophages. Subsequent in vitro studies showed that CA are phagocytosed and degraded by macrophages. We also observed that there may be redundant mechanisms involved in triggering the phagocytosis process, which would ensure the elimination of CA. Moreover, these mechanisms are related to non-inflammatory responses, which allow the elimination of CA without tissue damage. On the other hand, we pointed out that the NE present in CA, which may act as “eat-me” signals that would enhance the phagocytosis of CA, have a carbohydrate nature. Taken together, these findings support the above-mentioned hypothesis, indicating that CA can act as containers that remove waste products from the brain and are involved in a mechanism that cleans the CNS. According to these results, the present thesis was later extended to find out the function of the CA from other organs and tissues. In this regard, we aimed to establish a global and integrative hypothesis about the function and significance of CA in the whole organism. The results allowed us to suggest that CA in the different organs are created by specific cells, which collect waste products and amass them within a glycan structure, and secrete them into the external medium or interstitial spaces being, in this second case, phagocytosed by macrophages. Overall, we suggested considering CA from the different tissues of the human body as waste containers. Lastly, to avoid the ambiguity of the terms amyloid or amylacea (that indicate starch-like structures but can also refer to insoluble fibrillary proteins), we proposed renaming CA as “wasteosomes”, emphasizing the waste products they entrap rather than their misleading amyloid properties.[spa] Els corpora amylacea (CA) del cervell humà són uns agregats de poliglucosà que van ser descrits per primera vegada per J.E. Purkinje el 1837. Són cossos astrocítics intracel·lulars que s'acumulen principalment a les regions perivasculars, periventriculars i subpials del cervell durant l’envelliment, però també es troben en grans quantitats en àrees específiques del cervell en condicions neurodegeneratives. Diferents estudis postulen que la funció dels CA consisteix en atrapar productes residuals derivats de l'envelliment o processos degeneratius. Tot i que els CA estan essencialment constituïts per hexoses polimeritzades, principalment glucosa, s'han descrit una gran diversitat de components en els CA, com ara productes derivats de neurones, astròcits, oligodendrocits o de la sang, o fins i tot relacionats amb infeccions virals, fúngiques o microbianes. La seva localització a les regions perivasculars, periventriculars i subpials del cervell, totes elles connectades o properes a cavitats plenes de líquid cefalorraquidi (LCR), suggereix que els CA podrien ser extruïts des d'aquestes regions cap al LCR. A més, els CA contenen uns neo-epítops (NE) de naturalesa desconeguda que són reconeguts per anticossos naturals de tipus IgM. Aquesta interacció IgM-NE indica que si els CA fossin alliberats del sistema nerviós central (SNC), podrien interaccionar amb el sistema immunitari natural, el qual podria intervenir en la seva eliminació. Aquest conjunt d'evidències va permetre considerar que els CA no només recullen productes residuals, sinó que també actuen com a contenidors de substàncies de rebuig i estan involucrats en un mecanisme de neteja del SNC. D’acord amb això, la present tesi va tenir com a objectiu verificar aquesta hipòtesi. Els estudis realitzats van revelar la presència de CA al LCR i als ganglis limfàtics cervicals, als quals el LCR drena mitjançant el sistema limfàtic meningi. Als ganglis cervicals, es van observar CA en contacte amb algunes cèl·lules que, segons la seva localització, forma i propietats de tinció, podrien ser macròfags. Posteriorment, estudis in vitro van revelar que els CA són fagocitats i degradats pels macròfags. També es va observar que hi hauria mecanismes redundants involucrats en el desencadenament de la fagocitosi, cosa que asseguraria l'eliminació dels CA. A més, aquests mecanismes estan relacionats amb respostes no inflamatòries, que permeten eliminar la CA sense causar dany tissular. D'altra banda, es va determinar que els NE presents a CA, que poden actuar com a senyals eat-me que potenciarien la fagocitosi de CA, tenen naturalesa de glucídica. En conjunt, aquests resultats donen suport a la hipòtesi esmentada anteriorment, que indica que els CA poden actuar com a contenidors que eliminen productes de rebuig del cervell i estan involucrats en un mecanisme de neteja del SNC. D'acord amb aquests resultats, la tesi es va ser ampliada per estudiar també la funció dels CA presents a altres òrgans i teixits. En aquest aspecte, l’objectiu va ser establir una hipòtesi global i integradora sobre la funció i la significança dels CA de tot l'organisme. Els resultats van permetre suggerir que els CA dels diferents òrgans són generats per cèl·lules específiques, les quals recol·lecten productes de rebuig i els acumulen dins d'una estructura glucídica, i els secreten al medi extern o a espais intersticials sent, en aquest segon cas, fagocitats per macròfags. En general, es proposa que els CA del cos humà actuen com a contenidors de productes de rebuig. Finalment, per evitar l'ambigüitat dels termes amiloide o amylacea (que indiquen estructures similars al midó però també poden referir-se a proteïnes fibril·lars insolubles), es proposa canviar el nom dels CA a "wasteosomes", emfatitzant la captació de productes de rebuig en lloc dels seus confuses propietats amiloides

Analyzing the Virchow pioneering report on brain corpora amylacea: shedding light on recurrent controversies

The frst report of corpora amylacea (CA) is attributed to Morgagni, who described them in the prostate in the eighteenth century. Nearly a hundred years later, and following the lead started by Purkinje, Virchow described them in the brain. He made a detailed description of the most useful techniques to visualize them, but he failed to describe the cause of why CA do appear, why they are mainly linked with the elderly, and which is their clinical signifcance. Although in the last two centuries CA have received little attention, recent data have been able to describe that CA accumulate waste products and that some of them can be found in the cerebrospinal fuid and lymphatic nodes, after being released from the brain. Indeed, CA have been renamed to wasteosomes to underline the waste products they gather and to avoid confusion with the term amyloid used by Virchow, now widely related to certain protein deposits found in the brain. Here, after providing a commented English translation of Virchow's fndings, we provide a recent update on these structures and their connection with the glymphatic system insufciency, for which wasteosomes should be considered a hallmark, and how these bodies could serve as diagnostic or prognostic markers of various brain conditions