Microglial cathepsin E plays a role in neuroinflammation and amyloid β production in Alzheimer’s disease

Xie, Zhen; Meng, Jie; Kong, Wei; Wu, Zhou; Lan, Fei; Narengaowa,; Hayashi, Yoshinori; Yang, Qinghu; Bai, Zhan-Tao; Nakanishi, Hiroshi; Qing, Hong; Ni, Junjun

doi:10.1111/acel.13565

Cited by 20 publications

(12 citation statements)

References 45 publications

(66 reference statements)

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“…Ctse encodes for CatE, a protease involved in the endosomal-lysosomal system, is exclusively expressed by reactive microglia, and increases in response to amyloid pathology (52). The transcription factor PU.1 (encoded by Spi1), which was identified a female-biased upstream regulator in old microglia, enhances Ctse expression (53).…”

Section: Discussionmentioning

confidence: 99%

“…Cathepsin E ( Ctse ) was also found to be differentially expressed by sex in the old groups in our translatomic and translatomic analyses, as well as a previous study in the mouse forebrain (23). Ctse encodes for CatE, a protease involved in the endosomal-lysosomal system, is exclusively expressed by reactive microglia, and increases in response to amyloid pathology (52). The transcription factor PU.1 (encoded by Spi1 ), which was identified a female-biased upstream regulator in old microglia, enhances Ctse expression (53).…”

Section: Discussionmentioning

confidence: 99%

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Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease

Ocañas

Pham

Cox

et al. 2023

Preprint

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Background Microglia, the brain's principal immune cells, have been implicated in the pathogenesis of Alzheimer's disease (AD), a condition shown to affect more females than males. Although sex differences in microglial function and transcriptomic programming have been described across development and in disease models of AD, no studies have comprehensively identified the sex divergences that emerge in the aging mouse hippocampus. Further, existing models of AD generally develop pathology (amyloid plaques and tau tangles) early in life and fail to recapitulate the aged brain environment that is associated with late-onset AD. Here, we examined and compared the transcriptomic and translatomic sex effects in young and old mouse hippocampus. Methods Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5-6 month-old [mo]) and old (22-25 mo) ages. Cell sorting and affinity purification techniques were used to isolate the microglial transcriptome and translatome, respectively, for RNA-sequencing and differential expression analyses. Flow cytometry was used to confirm the transcriptomic findings. Results There were marginal sex differences identified in the young hippocampal microglia, with most differentially expressed genes (DEGs) restricted to the sex chromosomes. Both sex chromosomally- and autosomally-encoded sex differences emerge with aging. These sex DEGs identified at old age were primarily female-biased and were enriched in senescent and disease-associated microglial signatures. Pathway analysis identified upstream regulators induced to a greater extent in females than in males, including inflammatory mediators IFNG, TNF, and IL1B, as well as AD-risk genes TREM2 and APP. Conclusions These data suggest that female microglia adopt disease-associated and senescent phenotypes in the aging mouse hippocampus, even in the absence of disease pathology, to a greater extent than males. This sexually divergent microglial phenotype may explain the difference in susceptibility and disease progression in the case of AD pathology. Future studies will need to explore sex differences in microglial heterogeneity in response to AD pathology, and explore how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease

Ocañas

Pham

Cox

et al. 2023

Preprint

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“…Accumulating evidence suggests that the amyloid cascade and tau hyperphosphorylation cannot explain much of the pathogenesis of AD, indicating that other pathological processes, particularly neuroinflammation, are likely to be involved (Leng & Edison, 2021). Indeed, neuroinflammation is increasingly regarded as a key contributor to AD pathology (Ni et al, 2019; Wu et al, 2017; Xie, Meng, Kong, et al, 2022). Neuroinflammation in AD is primarily driven by CNS‐resident microglia (Zhao et al, 2018).…”

Section: Microglia Phagocytosis In Admentioning

confidence: 99%

“…Microglial phagocytosis is believed to be gradually compromised during the progression of AD, and this impairment has been shown to correlate with an increase in the production of proinflammatory cytokines and the overwhelming accumulation of Aβ plaques in the AD brain (Xie, Meng, Kong, et al, 2022). When investigating the relationship between proinflammatory cytokine production and Aβ phagocytosis, Babcock et al measured the phagocytic index and total Aβ load in cytokine‐producing and non‐cytokine‐producing subsets of CD11b + CD45 + microglia from the neocortex of 21‐month‐old APP/PS1 transgenic mice (Babcock et al, 2015).…”

Section: Microglia Phagocytosis In Admentioning

confidence: 99%

How brain ‘cleaners’ fail: Mechanisms and therapeutic value of microglial phagocytosis in Alzheimer's disease

Ni,

Xie,

Quan

et al. 2023

Glia

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Microglia are the resident phagocytes of the brain, where they primarily function in the clearance of dead cells and the removal of un‐ or misfolded proteins. The impaired activity of receptors or proteins involved in phagocytosis can result in enhanced inflammation and neurodegeneration. RNA‐seq and genome‐wide association studies have linked multiple phagocytosis‐related genes to neurodegenerative diseases, while the knockout of such genes has been demonstrated to exert protective effects against neurodegeneration in animal models. The failure of microglial phagocytosis influences AD‐linked pathologies, including amyloid β accumulation, tau propagation, neuroinflammation, and infection. However, a precise understanding of microglia‐mediated phagocytosis in Alzheimer's disease (AD) is still lacking. In this review, we summarize current knowledge of the molecular mechanisms involved in microglial phagocytosis in AD across a wide range of pre‐clinical, post‐mortem, ex vivo, and clinical studies and review the current limitations regarding the detection of microglia phagocytosis in AD. Finally, we discuss the rationale of targeting microglial phagocytosis as a therapeutic strategy for preventing AD or slowing its progression.

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“…Moreover toxic side effects, inappropriate dosage and timing of treatment, and reduced bioavailability have added to the obstacles (Yiannopoulou et al, 2019). Recent researches have revealed that apart from amyloid and tau burden, neuroinflammation, neuronal atrophy, loss of synaptic connectivity play crucial role in the pathogenesis and progression of AD (Xie et al, 2022). Therefore, multi-targeted and combinatorial therapies capable of reversing AD pathology as well as maintaining body homeostasis are considered as prospective treatment approach.…”

Section: Introductionmentioning

confidence: 99%

Preclinical efficacy of bacosides-lauric acid nano-herbal formulation in comparison to rivastigmine for treatment of Alzheimer’s disease

Kumar

Goyal

Pal

et al. 2022

Preprint

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Despite decades of rigorous scientific endeavors for Alzheimer’s disease (AD) drug development, massive failures in clinical trials is continuously posing healthcare and societal burden. Currently recommended single targeted drugs including rivastigmine with limited bioavailability can alleviate AD symptoms only for a limited period of time but unable to reverse the disease progression. Recent evidences consider poly-pharmacological and multi-targeted agents aiming at amyloid and tau burden, neuroinflammation, neuroprotection and cognitive enhancement as potential treatment options. In this regard, bioactive herbal compounds with holistic action and minimal adversities have gained prominence, though lacunae in their scientific validation and limited bio-permeability to cross BBB represent major hurdles. Previously, we showed that lactoferrin conjugated PEG-S-S-PLA-PCL-OH efficaciously delivered herbal compounds to brain and such nano-herbal formulation of bacosides-lauric acid (BAN-LAN) attenuated neuronal damages induced by scopolamine in vitro. Here, we tested the preclinical potential of BAN-LAN in reversal of AD pathologies in 5XFAD transgenic mice. Our nano-herbal formulation substantially reduced amyloid burden by clearing Aβ plaques in the hippocampus of 5XFAD mice and also attenuated aβ42 induced alterations in AD associated gene expression in hippocampal neurons in vitro. It showed neuroprotection by rescuing neuronal damage and promoting neurogenesis in the hippocampus of AD transgenic mice. Anti-neuroinflammatory properties were also exhibited by the formulation as evident from inhibition of hippocampal astrocytic and microglial activation in 5XFAD mice. BAN-LAN showed cognitive efficacy by restoring memory impairment in AD transgenic mice and effects were more pronounced than unconjugated natural form and rivastigmine. These findings suggest that BAN-LAN may serve as a promising therapeutic agent for AD with better brain penetration and targeting multiple AD pathways.

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Microglial cathepsin E plays a role in neuroinflammation and amyloid β production in Alzheimer’s disease

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 20 publications

References 45 publications

Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease

Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease

How brain ‘cleaners’ fail: Mechanisms and therapeutic value of microglial phagocytosis in Alzheimer's disease

Preclinical efficacy of bacosides-lauric acid nano-herbal formulation in comparison to rivastigmine for treatment of Alzheimer’s disease

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