抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer9s disease (AD) may be caused by deposition of amyloid β-peptide (Aβ) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Aβ production and Aβ clearance.

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The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics

Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...

Alzheimer's Disease: Genes, Proteins, and Therapy

Prospective Cohort Study

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.

For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.

Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

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Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Cette invention concerne le domaine des troubles du systeme nerveux peripherique et central, en particulier la maladie d'Alzheimer, ainsi que leur prevention et leur traitement. Plus particulierement, l'invention concerne ARF6 et/ou des proteines effectrices de ARF6 en tant que nouvelles cibles pour la maladie d'Alzheimer et, a partir de la, des procedes de criblage de composes qui reduisent la formation de peptides beta-amyloides dans des cellules de mammifere en agissant sur le tri endosomal induit par ARF6.

Arf6 en tant que nouvelle cible pour le traitement de la maladie d'alzheimer

The present invention relates to the field of cancer, more particularly to the field of lymphomas and even more particularly to the field of B- and T-cell tumors. The invention describes a transgenic mouse which does not produce the mitochondrial rhomboid like protease PARL. It is revealed that the phenotype of this mouse is characterized by a massive apoptosis in B- and T-cells. The invention thus relates to molecules which can bind to PARL and are capable of inducing apoptosis in B- and T-cells. The invention further relates to the use of these molecules to treat cancers of B- and T-cells, more commonly designated as lymphomas.

The mitochondrial rhomboid protease parl as a target for lymphoma

Purpose Previous research in the AppNL-G-F mouse has shown that hyperspectral retinal imaging (HSRI) can be used to quantify retinal amyloid burden in the preclinical stages of Alzheimer’s disease (AD) [1]. This underscores its potential as an imaging biomarker for AD diagnosis and monitoring. One prerequisite for the rational implementation of HSRI as a biomarker, however, is a better understanding of the pathological correlate of the HSRI signature. In this follow-up study, we explored HSRI signatures in different proteinopathies and identified the pathological features underlying the observed HSRI results. Methods Retinal tissues were collected from mouse models with amyloid, tau and alpha-synuclein overexpression/aggregation for ex vivo HSRI (Snapscan, Imec) [1]. HSRI was complemented with optical coherence tomography and electroretinograms (prior to HSRI) and immunohistochemistry and molecular studies of protein aggregation (after HSRI). Results While all protein aggregates led to HSRI changes in the 450–600 nm range, distinct signatures were observed for amyloid, tau and alpha-synuclein. Furthermore, the observed HSRI changes correlated with levels of the protein oligomerization and aggregation. Diverging patterns of retinal dysfunction/degeneration were observed in the different mouse models, illustrating the varied impacts of these protein aggregates on retinal structure and function. Conclusions HSRI may be used to quantify retinal amyloid, tau and alpha-synuclein, underscoring its potential as a biomarker for diagnosis and disease monitoring. Moreover, our data suggest that amyloid, tau and alpha-synuclein accumulation lead to distinct HSRI signatures, thus adding further evidence that HSRI may have utility in the diagnosis and stratification of proteinopathies associated with the most common forms of neurodegenerative diseases. Bibliograph Vandenabeele et al. (2021) Acta Neuropathol Commun 9(1):6. 

Bart De Strooper

Papers

Arf6 en tant que nouvelle cible pour le traitement de la maladie d'alzheimer

The mitochondrial rhomboid protease parl as a target for lymphoma

Hyperspectral retinal imaging in mouse models of proteinopathies identifies disease‐specific signatures