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The brain's choroid plexus (CP), which operates as an anatomical and functional 'checkpoint', regulates the communication between brain and periphery and contributes to the maintenance of healthy brain homeostasis throughout life. Evidence from mouse models and humans reveals a link between loss of CP checkpoint properties and dysregulation of the CP immune milieu as a conserved feature across diverse neurological conditions. In particular, we suggest that an imbalance between different immune signals at the CP, including CD4 + T cell-derived cytokines, type-I interferon, and complement components, can perpetuate brain inflammation and cognitive deterioration in aging and neurodegeneration. Furthermore, we highlight the role of CP metabolism in controlling CP inflammation, and propose that targeting molecules that regulate CP metabolism could be effective in safeguarding brain function., Competing Interests: Declaration of Interests M.S. is an inventor of the intellectual property that forms the basis for development of PD-L1 immunotherapy for AD. M.S. is the cofounder of ImmunoBrain Checkpoint (IBC). The other authors declare no competing interests in relation to this work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The choroid plexus (CP) plays a key role in remotely controlling brain function in health, aging, and disease. Here, we report that CP epithelial cells express the brain-specific cholesterol 24-hydroxylase (CYP46A1) and that its levels are decreased under different mouse and human brain conditions, including amyloidosis, aging, and SARS-CoV-2 infection. Using primary mouse CP cell cultures, we demonstrate that the enzymatic product of CYP46A1, 24(S)-hydroxycholesterol, downregulates inflammatory transcriptomic signatures within the CP, found here to be elevated across multiple neurological conditions. In vitro, the pro-inflammatory cytokine tumor necrosis factor α (TNF-α) downregulates CYP46A1 expression, while overexpression of CYP46A1 or its pharmacological activation in mouse CP organ cultures increases resilience to TNF-α. In vivo, overexpression of CYP46A1 in the CP in transgenic mice with amyloidosis is associated with better cognitive performance and decreased brain inflammation. Our findings suggest that CYP46A1 expression in the CP impacts the role of this niche as a guardian of brain immune homeostasis., Competing Interests: Declaration of interests M.S. is an inventor of the intellectual property that forms the basis for the development of PD-L1 immunotherapy for AD., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Systemic immunity supports lifelong brain function. Obesity posits a chronic burden on systemic immunity. Independently, obesity was shown as a risk factor for Alzheimer's disease (AD). Here we show that high-fat obesogenic diet accelerated recognition-memory impairment in an AD mouse model (5xFAD). In obese 5xFAD mice, hippocampal cells displayed only minor diet-related transcriptional changes, whereas the splenic immune landscape exhibited aging-like CD4 + T-cell deregulation. Following plasma metabolite profiling, we identified free N-acetylneuraminic acid (NANA), the predominant sialic acid, as the metabolite linking recognition-memory impairment to increased splenic immune-suppressive cells in mice. Single-nucleus RNA-sequencing revealed mouse visceral adipose macrophages as a potential source of NANA. In vitro, NANA reduced CD4 + T-cell proliferation, tested in both mouse and human. In vivo, NANA administration to standard diet-fed mice recapitulated high-fat diet effects on CD4 + T cells and accelerated recognition-memory impairment in 5xFAD mice. We suggest that obesity accelerates disease manifestation in a mouse model of AD via systemic immune exhaustion., (© 2023. The Author(s).)

The type I interferon (IFN) response is the body's typical immune defense against viruses. Previous studies linked high expression of genes encoding type I IFNs in the brain's choroid plexus to cognitive decline under virus-free conditions in aging and neurodegeneration. Multiple reports have documented persisting cognitive symptoms following recovery from COVID-19. Cumulative evidence shows that the choroid plexus is one of the brain regions most vulnerable to infection with the coronavirus SARS-CoV-2, and manifests increased expression of genes encoding type I IFNs even in the absence of viral traces within the brain. In this Perspective, we propose that the type I IFN defensive immune response to SARS-CoV-2 infection in the choroid plexus poses a risk to cognitive function if not resolved in a timely manner., (© 2023. Springer Nature America, Inc.)

Recent functional and anatomical discoveries of brain-immune relationships have overturned previous beliefs regarding the brain's immune privilege. Here, we propose that the brain and immune cells at its borders operate as an "ecosystem" to support the brain's robustness and resilience. Modulation of this ecosystem can be harnessed in the clinic., Competing Interests: Declaration of interests Michal Schwartz is an inventor of the intellectual property that forms the basis for development of anti-PD-L1 immunotherapy for AD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

LRRK2 gain-of-function is considered a major cause of Parkinson's disease (PD) in humans. However, pathogenicity of LRRK2 loss-of-function in animal models is controversial. Here we show that deletion of the entire zebrafish lrrk2 locus elicits a pleomorphic transient brain phenotype in maternal-zygotic mutant embryos (mzLrrk2). In contrast to lrrk2, the paralog gene lrrk1 is virtually not expressed in the brain of both wild-type and mzLrrk2 fish at different developmental stages. Notably, we found reduced catecholaminergic neurons, the main target of PD, in specific cell populations in the brains of mzLrrk2 larvae, but not adult fish. Strikingly, age-dependent accumulation of monoamine oxidase (MAO)-dependent catabolic signatures within mzLrrk2 brains revealed a previously undescribed interaction between LRRK2 and MAO biological activities. Our results highlight mzLrrk2 zebrafish as a tractable tool to study LRRK2 loss-of-function in vivo, and suggest a link between LRRK2 and MAO, potentially of relevance in the prodromic stages of PD., Competing Interests: The authors have declared that no competing interests exist.

The study of neurogenesis during chronic neurodegeneration is crucial in order to understand the intrinsic repair mechanisms of the brain, and key to designing therapeutic strategies. In this study, using an experimental model of progressive chronic neurodegeneration, murine prion disease, we define the temporal dynamics of the generation, maturation and integration of new neurons in the hippocampal dentate gyrus, using dual pulse-chase, multicolour γ-retroviral tracing, transmission electron microscopy and patch-clamp. We found increased neurogenesis during the progression of prion disease, which partially counteracts the effects of chronic neurodegeneration, as evidenced by blocking neurogenesis with cytosine arabinoside, and helps to preserve the hippocampal function. Evidence obtained from human post-mortem samples, of both variant Creutzfeldt-Jakob disease and Alzheimer's disease patients, also suggests increased neurogenic activity. These results open a new avenue into the exploration of the effects and regulation of neurogenesis during chronic neurodegeneration, and offer a new model to reproduce the changes observed in human neurodegenerative diseases., (© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.)

A multidisciplinary effort involving epidemiologists, general practitioners and specialists is critical for finding valid and feasible answers, by asking the right questions through observational and experimental studies. Clinical practice guidelines may represent a good starting point of this research process, highlighting which information needs exist in everyday practice; logically, guidelines also represent an ideal end, as a means of transferring any useful knowledge produced into practice. In between, this research process may have an added educational value and represent an active and valuable means of achieving continuing medical education credits. Consistency of the research-education-guidelines triad is discussed in this paper by describing methods and results of a practical research experience--a cohort study for evaluating prevalence, incidence, chronicity and management of digestive disorders--involving epidemiologists, gastroenterologists and thirty-five general practitioners of the Emilia-Romagna region.