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Corpora amylacea are spherical bodies of unknown origin and function, which accumulate in the human brain during the aging process and neurodegenerative disorders. In recent work, we reported that they contain some neo-epitopes that are recognized by natural IgMs, revealing a possible link between them and the natural immune system. Here, we performed an ultrastructural study complemented with confocal microscopy in order to shed light on the formation of corpora amylacea and to precisely localize the neo-epitopes. We show that immature corpora amylacea are intracellular astrocytic structures formed by profuse cellular debris and membranous blebs entrapped in a scattered mass of randomly oriented short linear fibers. In mature corpora amylacea, the structure becomes compacted and fibrillary material constitutes the principal component. We also determined that the neo-epitopes were uniformly localized throughout the whole structure. All these observations reinforce the idea that corpora amylacea of human brain are equivalent to another type of polyglucosan bodies named PAS granules, present in mouse brain and originated from degenerative processes. All those findings support the hypothesis that corpora amylacea are involved in the entrapment of damaged materials and non-degradable products and have a role in protective or cleaning mechanisms.

Corpora amylacea (CA) are polyglucosan bodies that accumulate in the human brain during ageing and are also present in large numbers in neurodegenerative conditions. Theories regarding the function of CA are regularly updated as new components are described. In previous work, we revealed the presence of some neo-epitopes in CA and the existence of some natural IgM antibodies directed against these neo-epitopes. We also noted that these neo-epitopes and IgMs were the cause of false staining in CA immunohistochemical studies, and disproved the proposed presence of β-amyloid peptides and tau protein in them. Here we extend the list of components erroneously attributed to CA. We show that, contrary to previous descriptions, CA do not contain GFAP, S100, AQP4, NeuN or class III β-tubulin, and we question the presence of other components. Nonetheless, we observe that CA contains ubiquitin and p62, both of them associated with processes of elimination of waste substances, and also glycogen synthase, an indispensable enzyme for polyglucosan formation. In summary, this study shows that it is imperative to continue reviewing previous studies about CA but, more importantly, it shows that the vision of CA as structures involved in protective or cleaning mechanisms remains the most consistent theory.

Corpora amylacea (CA) in the human brain are polyglucosan bodies that accumulate residual substances originated from aging and both neurodegenerative and infectious processes. These structures, which act as waste containers, are released from the brain to the cerebrospinal fluid, reach the cervical lymph nodes via the meningeal lymphatic system and may be phagocytosed by macrophages. Recent studies indicate that CA present certain neoepitopes (NEs) that can be recognized by natural antibodies of the IgM class, and although evidence of different kinds suggests that these NEs may be formed by carbohydrate structures, their precise nature is unknown. Here, we adapted standard techniques to examine this question. We observed that the preadsorption of IgMs with specific carbohydrates has inhibitory effects on the interaction between IgMs and CA, and found that the digestion of CA proteins had no effect on this interaction. These findings point to the carbohydrate nature of the NEs located in CA. Moreover, the present study indicates that, in vitro , the binding between certain natural IgMs and certain epitopes may be disrupted by certain monosaccharides. We wonder, therefore, whether these inhibitions may also occur in vivo . Further studies should now be carried out to assess the possible in vivo effect of glycemia on the reactivity of natural IgMs and, by extension, on natural immunity.

Corpora amylacea (CA) in the human brain are granular bodies formed by polyglucosan aggregates that amass waste products of different origins. They are generated by astrocytes, mainly during aging and neurodegenerative conditions, and are located predominantly in periventricular and subpial regions. This study shows that CA are released from these 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.

Corpora amylacea are structures of unknown origin and function that appear with age in human brains and are profuse in selected brain areas in several neurodegenerative conditions. They are constituted of glucose polymers and may contain waste elements derived from different cell types. As we previously found on particular polyglucosan bodies in mouse brain, we report here that corpora amylacea present some neo-epitopes that can be recognized by natural antibodies, a certain kind of antibodies that are involved in tissue homeostasis. We hypothesize that corpora amylacea , and probably some other polyglucosan bodies, are waste containers in which deleterious or residual products are isolated to be later eliminated through the action of the innate immune system. In any case, the presence of neo-epitopes on these structures and the existence of natural antibodies directed against them could become a new focal point for the study of both age-related and degenerative brain processes.

Due to the physical and physiological properties of the blood–brain barrier (BBB), the transport of neurotherapeutics from blood to brain is still a pharmaceutical challenge. We previously conducted a series of experiments to explore the potential of the anti-transferrin receptor 8D3 monoclonal antibody (mAb) to transport neurotherapeutics across the BBB. In that study, gold nanoparticles (AuNPs) were coated with the 8D3 antibody and administered intravenously to mice. Transmission electron microscopy was used and a two-dimensional (2D) image analysis was performed to detect the AuNPs in the brain capillary endothelial cells (BCECs) and brain parenchyma. In the present work, we determined that serial block-face scanning electron microscopy (SBF-SEM) is a useful tool to study the transcytosis of these AuNPs across the BBB in three dimensions and we, therefore, applied it to gain more knowledge of their transcellular trafficking. The resulting 3D reconstructions provided additional information on the endocytic vesicles containing AuNPs and the endosomal processing that occurs inside BCECs. The passage from 2D to 3D analysis reinforced the trafficking model proposed in the 2D study, and revealed that the vesicles containing AuNPs are significantly larger and more complex than described in our 2D study. We also discuss tradeoffs of using this technique for our application, and conclude that together with other volume electron microscopy imaging techniques, SBF-SEM is a powerful approach that is worth of considering for studies of drug transport across the BBB.

Background Degenerative granular structures appear progressively with age in the hippocampus of most mouse strains. We recently reported that these granules contain a neo-epitope that is recognised by IgM antibodies present as contaminants in many commercial antibodies obtained from mouse ascites and mouse or rabbit serum. We hypothesise that these anti-neo-epitope IgMs are in fact natural auto-antibodies that are generated spontaneously during the foetal stage without previous contact with external antigens and whose repertoire and reactivity pattern have been determined through evolution, being remarkably stable within species and even between species. Findings In the present work we found that mice from the ICR-CD1, BALB/C and SAMP8 strains have anti-neo-epitope IgM antibodies in their plasma at all ages tested and even when maintained under specific opportunistic pathogen-free conditions. Moreover, we determined that these anti-neo-epitope IgMs are also present in rabbit, goat and rat serum. We also found that, in each mouse that presented hippocampal granules, the anti-neo-epitope IgMs contained in its plasma recognised the neo-epitopes in its own granules. Conclusions This study led to the conclusion that anti-neo-epitope IgMs are widespread natural auto-antibodies contained in the plasma of mice and other species. The presence of these natural auto-antibodies not only explains why they are frequently found as contaminants in commercial antibodies, but also paves the way for a new approach to a treatment and diagnosis of pathological brain processes based on natural IgMs and neo-epitopes.

The term polyglucosan bodies (PGBs) refers to complex aggregates composed of relatively large glucose polymers reaching diameters of tens of micrometres. PGBs have been reported in the central nervous system, but also in other organs and tissues, such as heart, skeletal muscle and liver. These aggregates have been described in humans and other species and they have been most widely studied in mammals. Different forms of PGBs have been related to particular situations or specific diseases. During the ageing process, human brain accumulates one type of PGBs called corpora amylacea (CA). Although CA have been studied for several years, their origin and function remain unclear. PGBs are also associated with Lafora disease, a neurodegenerative disorder that is characterized by the presence of PGBs structures called Lafora bodies (LBs). On the other hand, brain ageing in mice leads to the progressive appearance and expansion of degenerative granular PGBs frequently referred to as Periodic Acid Schiff (PAS) granules. These granules, which are present mainly in the hippocampus, originate in astrocytes processes and tend to appear in clusters. Each cluster corresponds to the set of granules of a determined astrocyte. Recently, our research group have reported the presence of neo-epitopes recognized by IgMs on these structures. These IgMs, which are present as contaminants in many commercial antibodies, are responsible of numerous false positive staining on these bodies when immunohistochemical procedures are used.This thesis aimed to study the origin, composition and function of PGBs that appear with age and in neurodegenerative conditions such as Alzheimer’s disease and Lafora disease.The results show that CA are similar structures to PAS granules from mice brain and that CA also contain neo-epitopes. In both cases, the neo-epitopes can be recognized by natural IgM antibodies, suggesting a new relation between PGBs and the natural immune system. Moreover, the false staining produced by the natural IgMs that bind to the neoepitopes clarified some controversial results previously described about the presence of some components on CA and their function. We also determined that CA accumulate non-degradable products generated during ageing process and increased in neurodegenerative condictiones, such as Alzheimer’s disease. Taking all into account, we hypothesize that CA are waste containers in which deleterious or residual products are isolated to be later eliminated through the action of the innate immune system. On the other hand, we observed that malin deficient mice, a mouse model of Lafora disease, present high amounts of two distinct types of PGBs: PAS granules or CA-like granules, originated in astrocytes and containing neo-epitopes, and neuronal LBs, which are exclusive of Lafora disease and do not contain neo-epitopes. Thus, the absence of malin triggers the formation of PGBs in neurons but also enhances their development in astrocytes. We postulate that, against to the current believe, astrocytes are involved in the etiopathogenesis of Lafora disease.Overall results show that the distinct PGBs have been studied until now with a specific and limited perspective. A global or main picture is necessary to obtain the knowledgement of their significance.

The efficacy of oxaliplatin in cancer chemotherapy is limited by the development of drug resistance. MMP7 has been related to the loss of tumor cell response to cytotoxic agents although the exact mechanism is not fully understood. Moreover, MMP7 is an independent prognosis factor for survival in patients with colorectal cancer. The aim of the present study was to analyze the role of MMP7 and its cross-talk with the Fas/FasL system during the acquisition of oxaliplatin resistance in colon cancer cells. For this purpose we have developed three different oxaliplatin-resistant cell lines (RHT29, RHCT116 p53(+/+), RHCT116 p53(-/-)) from the parental HT29, HCT116 p53(+/+) and HCT116 p53(-/-) colon cancer cells. MMP7 basal expression was higher in the resistant compared to the parental cell lines. MMP7 was also upregulated by oxaliplatin in both HT29 (p53 mutant) and RHCT116 p53(-/-) but not in the RHCT116 p53(+/+). Inhibition of MMP by 1,10-phenantroline monohydrate or siRNA of MMP7 restores cell sensitivity to oxaliplatin-induced apoptosis in both HT29 and RHCT116 p53(-/-) but not in the RHCT116 p53(+/+). Some of these effects are caused by alterations in Fas receptor. Fas is upregulated by oxaliplatin in colon cancer cells, however the RHT29 cells treated with oxaliplatin showed a 3.8-fold lower Fas expression at the cell surface than the HT29 cells. Decrease of Fas at the plasma membrane seems to be caused by MMP7 since its inhibition restores Fas levels. Moreover, functional analysis of Fas demonstrates that this receptor was less potent in inducing apoptosis in RHT29 cells and that its activation induces MAPK signaling in resistant cells. Taking together, these results suggest that MMP7 is related to the acquisition of oxaliplatin-resistance and that its inhibition restores drug sensitivity by increasing Fas receptor. Furthermore, Fas undergoes a change in its functionality in oxaliplatin-resistant cells inducing survival pathways instead of apoptotic signals.