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      Microglial cathepsin B as a key driver of inflammatory brain diseases and brain aging

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          Abstract

          Interleukin-1β is a potent proinflammatory cytokine that plays a key role in the pathogenesis of the brain aging and diverse range of neurological diseases including Alzheimer’s disease, Parkinson’s disease, stroke and persistent pain. Activated microglia are the main cellular source of interleukin-1β in the brain. Cathepsin B is associated with the production and secretion of interleukin-1β through pyrin domain-containing protein 3 inflammasome-independent processing of procaspase-3 in the phagolysosomes. The leakage of cathepsin B from the endosomal-lysosomal system during aging is associated with the proteolytic degradation of mitochondrial transcription factor A, which can stabilize mitochondrial DNA. Therefore, microglial cathepsin B could function as a major driver for inflammatory brain diseases and brain aging. Orally active and blood-brain barrier-permeable specific inhibitors for cathepsin B can be potentially effective new pharmaceutical interventions against inflammatory brain diseases and brain aging.

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          Running-Induced Systemic Cathepsin B Secretion Is Associated with Memory Function.

          Hyo Youl Moon, Andreas Becke, David Berron … (2016)
          Peripheral processes that mediate beneficial effects of exercise on the brain remain sparsely explored. Here, we show that a muscle secretory factor, cathepsin B (CTSB) protein, is important for the cognitive and neurogenic benefits of running. Proteomic analysis revealed elevated levels of CTSB in conditioned medium derived from skeletal muscle cell cultures treated with AMP-kinase agonist AICAR. Consistently, running increased CTSB levels in mouse gastrocnemius muscle and plasma. Furthermore, recombinant CTSB application enhanced expression of brain-derived neurotrophic factor (BDNF) and doublecortin (DCX) in adult hippocampal progenitor cells through a mechanism dependent on the multifunctional protein P11. In vivo, in CTSB knockout (KO) mice, running did not enhance adult hippocampal neurogenesis and spatial memory function. Interestingly, in Rhesus monkeys and humans, treadmill exercise elevated CTSB in plasma. In humans, changes in CTSB levels correlated with fitness and hippocampus-dependent memory function. Our findings suggest CTSB as a mediator of effects of exercise on cognition.
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            Microglia turnover with aging and in an Alzheimer's model via long-term in vivo single-cell imaging

            Petra Füger, Bettina M Wegenast-Braun, Jonas J. Neher … (2017)
            Neocortical resident microglia are long-lived cells. Füger et al. report that approximately half of these cells survive for the entire lifespan of a mouse. While microglial proliferation under homeostatic conditions is low, proliferation is increased in a mouse model of Alzheimer's disease.
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              Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

              Monica Elmore, Lindsay A. Hohsfield, Enikö A Kramár … (2018)
              Abstract Microglia, the resident immune cell of the brain, can be eliminated via pharmacological inhibition of the colony‐stimulating factor 1 receptor (CSF1R). Withdrawal of CSF1R inhibition then stimulates microglial repopulation, effectively replacing the microglial compartment. In the aged brain, microglia take on a “primed” phenotype and studies indicate that this coincides with age‐related cognitive decline. Here, we investigated the effects of replacing the aged microglial compartment with new microglia using CSF1R inhibitor‐induced microglial repopulation. With 28 days of repopulation, replacement of resident microglia in aged mice (24 months) improved spatial memory and restored physical microglial tissue characteristics (cell densities and morphologies) to those found in young adult animals (4 months). However, inflammation‐related gene expression was not broadly altered with repopulation nor the response to immune challenges. Instead, microglial repopulation resulted in a reversal of age‐related changes in neuronal gene expression, including expression of genes associated with actin cytoskeleton remodeling and synaptogenesis. Age‐related changes in hippocampal neuronal complexity were reversed with both microglial elimination and repopulation, while microglial elimination increased both neurogenesis and dendritic spine densities. These changes were accompanied by a full rescue of age‐induced deficits in long‐term potentiation with microglial repopulation. Thus, several key aspects of the aged brain can be reversed by acute noninvasive replacement of microglia.
              Article 0 comments Cited 150 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Neural Regen Res
                Journal ID (iso-abbrev): Neural Regen Res
                Journal ID (publisher-id): NRR
                Title: Neural Regeneration Research
                Publisher: Wolters Kluwer - Medknow (India )
                ISSN (Print): 1673-5374
                ISSN (Electronic): 1876-7958
                Publication date Collection: January 2020
                Publication date (Electronic): 16 September 2019
                Volume: 15
                Issue: 1
                Pages: 25-29
                Affiliations
                [1]Department of Pharmacology, Faculty of Pharmacy, Yasuda Women's University, Hiroshima, Japan
                Author notes
                [* ] Correspondence to: Hiroshi Nakanishi, nakanishi-h@ 123456yasuda-u.ac.jp .

                Author contributions: HN conceived and wrote this review entirely.

                Author information
                http://orcid.org/0000-0001-5671-9696
                Article
                Publisher ID: NRR-15-25
                DOI: 10.4103/1673-5374.264444
                PMC ID: 6862407
                PubMed ID: 31535638
                SO-VID: 9830e14f-f331-476e-b850-052ce4f51117
                Copyright © Copyright: © Neural Regeneration Research
                License:

                This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

                History
                Date received : 28 March 2019
                Date accepted : 14 May 2019
                Categories
                Subject: Review

                Keywords: brain aging,caspase-1,cathepsin b,inflammatory brain diseases,interleukin-1β,microglia,mitochondrial transcription factor a,neuroinflammation; nuclear factor-κβ,oxidative stress
                Data availability:
                Keywords: brain aging, caspase-1, cathepsin b, inflammatory brain diseases, interleukin-1β, microglia, mitochondrial transcription factor a, neuroinflammation; nuclear factor-κβ, oxidative stress

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