Microbes have been suspected to cause Alzheimer’s disease since at least 1908, but this has generally remained unpopular in comparison to the amyloid hypothesis and the dominance of Aβ and Tau. However, evidence has been accumulating to suggest that these earlier theories are but a manifestation of a common cause that can trigger and interact with all the major molecular players recognized in AD. Aβ, Tau and ApoE, in particular appear to be molecules with normal homeostatic functions but also with alternative antimicrobial functions. Their alternative functions confer the non-immune specialized neuron with some innate intracellular defenses that appear to be re-appropriated from their normal functions in times of need. Indeed, signs of infection of the neurons by biofilm-forming microbial colonies, in synergy with herpes viruses, are evident from the clinical and preclinical studies we discuss. Furthermore, we attempt to provide a mechanistic understanding of the AD landscape by discussing the antimicrobial effect of Aβ, Tau and ApoE and Lactoferrin in AD, and a possible mechanistic link with deficiency of vital copper-based systems. In particular, we focus on mitochondrial oxidative respiration via complex 4 and ceruloplasmin for iron homeostasis, and how this is similar and possibly central to neurodegenerative diseases in general. In the case of AD, we provide evidence for the microbial Alzheimer’s disease (MAD) theory, namely that AD could in fact be caused by a long-term microbial exposure or even long-term infection of the neurons themselves that results in a costly prolonged antimicrobial response that disrupts copper-based systems that govern neurotransmission, iron homeostasis and respiration. Finally, we discuss potential treatment modalities based on this holistic understanding of AD that incorporates the many separate and seemingly conflicting theories. If the MAD theory is correct, then the reduction of microbial exposure through use of broad antimicrobial and anti-inflammatory treatments could potentially alleviate AD although this requires further clinical investigation. 

MAD—microbial (origin of) Alzheimer’s disease hypothesis: from infection and the antimicrobial response to disruption of key copper-based systems

This review aims to clarify the nature of the link between Alzheimer’s disease and the oral microbiome on an epidemiological and pathophysiological level, as well as to highlight new therapeutic perspectives that contribute to the management of this disease. We performed a systematic review, following the Preferred Reporting Items for Systematic Reviews checklist, from January 2000 to July 2021. The terms “plaque,” “saliva,” and “mouth” were associated with the search term “oral diseases” and used in combination with the Boolean operator “AND”/“OR”. We included experimental or clinical studies and excluded conferences, abstracts, reviews, and editorials. A total of 27 articles were selected. Evidence for the impact of the oral microbiome on the pathophysiological and immunoinflammatory mechanisms of Alzheimer’s disease is accumulating. The impact of the oral microbiome on the development of AD opens the door to complementary therapies such as phototherapy and/or the use of prebiotic compounds and probiotic strains for global or targeted modulation of the oral microbiome in order to have a favourable influence on the evolution of this pathology in the future.

/pdf/evidence-and-therapeutic-perspectives-in-the-relationship-2y8eemiww9.pdf

Evidence and Therapeutic Perspectives in the Relationship between the Oral Microbiome and Alzheimer's Disease: A Systematic Review.

ABSTRACT Glycosaminoglycans are often deprioritized as targets for synthetic immunotherapy due to the complexity of glyco-epitopes and limited options for obtaining specific subtype-binding. Solid tumors express proteoglycans that are modified with oncofetal chondroitin sulfate (CS), a modification normally restricted to the placenta. Here, we report the design and functionality of conditional chimeric antigen receptor (CAR) T cells with selectivity to oncofetal CS. Following expression in T cells, the CAR could be ‘armed’ with recombinant VAR2CSA lectins (rVAR2) to target tumor cells expressing oncofetal CS. While un-armed CAR T cells remained inactive in the presence of target cells, VAR2-armed CAR T cells displayed robust activation and the ability to eliminate diverse tumor cell types in vitro . Cytotoxicity of the CAR T cells was proportional to the concentration of rVAR2 available to the CAR, offering a potential molecular handle to finetune CAR T cell activity. In vivo , armed CAR T cells rapidly targeted bladder tumors and increased survival of tumor-bearing mice. Thus, our work indicates that cancer-restricted glycosaminoglycans can be exploited as potential targets for CAR T cell therapy. 

pdf/conditional-car-t-cells-with-specificity-to-oncofetal-17g6byg99i.pdf

Conditional CAR T cells with specificity to oncofetal glycosaminoglycans in solid tumors

Abstract Glycosaminoglycans are often deprioritized as targets for synthetic immunotherapy due to the complexity of glyco-epitopes and limited options for obtaining specific subtype binding. Solid tumors express proteoglycans that are modified with oncofetal chondroitin sulfate (CS), a modification normally restricted to the placenta. Here, we report the design and functionality of transient chimeric antigen receptor (CAR) T cells with selectivity to oncofetal CS. Following expression in T cells, the CAR could be “armed” with recombinant VAR2CSA lectins (rVAR2) to target tumor cells expressing oncofetal CS. While unarmed CAR T cells remained inactive in the presence of target cells, VAR2-armed CAR T cells displayed robust activation and the ability to eliminate diverse tumor cell types in vitro. Cytotoxicity of the CAR T cells was proportional to the concentration of rVAR2 available to the CAR, offering a potential molecular handle to finetune CAR T cell activity. In vivo, armed CAR T cells rapidly targeted bladder tumors and increased the survival of tumor-bearing mice. Thus, our work indicates that cancer-restricted glycosaminoglycans may be exploited as potential targets for CAR T cell therapy. 

Transient CAR T cells with specificity to oncofetal glycosaminoglycans in solid tumors

Background Recently, research on the microbiota-gut-brain axis (MGBA) has received increasing attention, and the number of studies related to Alzheimer’s disease (AD) has increased rapidly, but there is currently a lack of summary of MGBA in AD. Objective To capture research hotspots, grasp the context of disciplinary research, and explore future research development directions. Methods In the core dataset of Web of Science, documents are searched according to specific subject words. CiteSpace software is used to perform statistical analysis on measurement indicators such as the number of published papers, publishing countries, institutions, subject areas, authors, cocited journals, and keywords, and to visualize of a network of relevant content elements. Results The research of MGBA in AD has shown an upward trend year by year, and the cooperation between countries is relatively close, and mainly involves the intersection of neuroscience, pharmacy, and microbiology. This research focuses on the relationship between MGBA and AD symptoms. Keyword hotspots are closely related to new technologies. Alzheimer’s disease, anterior cingulate cortex, inflammatory degeneration, dysbiosis, and other research are the focus of this field. Conclusion The study revealed that the research and development of MGBA in AD rapidly progressed, but no breakthrough has been made in the past decade, it still needs to be closely combined with multidisciplinary technology to grasp the frontier hotspots. Countries should further strengthen cooperation, improve the disciplinary system, and increase the proportion of empirical research in all research.

/pdf/research-trend-of-microbiota-gut-brain-axis-in-alzheimers-3du3a8hg.pdf

Research trend of microbiota-gut-brain axis in Alzheimer’s disease based on CiteSpace (2012–2021): A bibliometrics analysis of 608 articles

Antimicrobial therapy and the potential mechanisms in Alzheimer's disease.

B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood malignancy. The cure rate has reached 90% after conventional chemotherapy and hematopoietic stem cell transplantation (HSCT), but the prognosis of patients with relapsed and refractory (R/R) leukemia is still poor after conventional treatment. Since FDA approved CD19 CAR-T cell (Kymriah) for the treatment of R/R B-ALL, increasing studies have been conducted on CAR-T cells for R/R ALL. Herein, we report the treatment of a patient with ALL who relapsed after allogeneic HSCT, had a complete remission (CR) to murine scFv CD19 CAR-T but relapsed 15 months later. Partial response was achieved after humanized CD19 CAR-T treatment, and the patient finally achieved disease-free survival after sequential CD22 CAR-T treatment. By comparing the treatment results of different CAR-T cells in the same patient, this case suggests that multiple CAR-T therapies are effective and safe in intramedullary and extramedullary recurrence in the same patient, and the expansion of CAR-T cells and the release of inflammatory cytokines are positively correlated with their efficacy. However, further clinical studies with large sample sizes are still needed for further clarification.

Multiple CAR-T cell therapy for acute B-cell lymphoblastic leukemia after hematopoietic stem cell transplantation: A case report

Plasma Proteomics To Identify the Biomarkers and Pathogenesis of Mild Cognitive Impairment

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Antimicrobial therapy and the potential mechanisms in Alzheimer's disease.

Multiple CAR-T cell therapy for acute B-cell lymphoblastic leukemia after hematopoietic stem cell transplantation: A case report

Plasma Proteomics To Identify the Biomarkers and Pathogenesis of Mild Cognitive Impairment