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Cathepsin B Promotes Aβ Proteotoxicity by Modulating Aging Regulating Mechanisms

ABSTRACT: While the activities of certain proteases promote proteostasis and prevent neurodegeneration-associated phenotypes, the protease cathepsin B (CTSB) enhances proteotoxicity in Alzheimer’s disease (AD) model mice, and its levels are elevated in brains of AD patients. How CTSB exacerbates the toxicity of the AD-causing Amyloid β (Aβ), is controversial. Using an activity based probe, aging-altering interventions and the nematode C. elegans we discovered that the CTSB CPR-6 promotes Aβ proteotoxicity but mitigates the toxicity of polyQ stretches. While the knockdown of cpr-6 does not affect lifespan, it alleviates Aβ toxicity by reducing the expression of swsn-3 and elevating the level of the protein SMK-1, both involved in the regulation of aging. These observations unveil a novel mechanism by which CTSB aggravates Aβ–mediated toxicity, indicate that it plays opposing roles in the face of distinct proteotoxic insults and highlight the importance of tailoring specific remedies for distinct neurodegenerative disorders.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE232889 | GEO | 2024/09/03

REPOSITORIES: GEO

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Cathepsin B Promotes Aβ Proteotoxicity by Modulating Aging Regulating Mechanisms

Project description:While the activities of certain proteases promote proteostasis and prevent neurodegeneration-associated phenotypes, the protease cathepsin B (CTSB) enhances proteotoxicity in Alzheimer’s disease (AD) model mice, and its levels are elevated in brains of AD patients. How CTSB exacerbates the toxicity of the AD-causing Amyloid β (Aβ), is controversial. Using an activity-based probe, aging-altering interventions and the nematode C. elegans we discovered that the CTSB CPR-6 promotes Aβ proteotoxicity but mitigates the toxicity of polyQ stretches. While the knockdown of cpr-6 does not affect lifespan, it alleviates Aβ toxicity by reducing the expression of swsn-3 and elevating the level of the protein SMK-1, both involved in the regulation of aging. These observations unveil a novel mechanism by which CTSB aggravates Aβ–mediated toxicity, indicate that it plays opposing roles in the face of distinct proteotoxic insults and highlight the importance of tailoring specific remedies for distinct neurodegenerative disorders.

2024-09-03 | PXD045531 | Pride

Cathepsin B Promotes Aβ Proteotoxicity by Modulating Aging Regulating Mechanisms

2024-09-03 | PXD045565 | Pride

Cathepsin B Promotes Aβ Proteotoxicity by Modulating Aging Regulating Mechanisms

Project description:While the activities of certain proteases promote proteostasis and prevent neurodegeneration-associated phenotypes, the protease cathepsin B (CTSB) enhances proteotoxicity in Alzheimer’s disease (AD) model mice, and its levels are elevated in brains of AD patients. How CTSB exacerbates the toxicity of the ADcausing Amyloid β (Aβ), is controversial. Using an activity-based probe, aging-altering interventions and the nematode C. elegans we discovered that the CTSB CPR-6 promotes Aβ proteotoxicity but mitigates the toxicity of polyQ stretches. While the knockdown of cpr-6 does not affect lifespan, it alleviates Aβ toxicity by reducing the expression of swsn-3 and elevating the level of the protein SMK-1, both involved in the regulation of aging. These observations unveil a novel mechanism by which CTSB aggravates Aβ– mediated toxicity, indicate that it plays opposing roles in the face of distinct proteotoxic insults and highlight the importance of tailoring specific remedies for distinct neurodegenerative disorders.

2024-09-04 | PXD045561 | Pride

A Short Peptide Protects from Age-Onset Proteotoxicity

Project description:Aberrant protein aggregation jeopardize cellular functionality and underlies the development of a myriad of late-onset maladies including Alzheimer’s disease (AD) and Huntington’s disease (HD). Accordingly, molecules that mitigate the toxicity of hazardous protein aggregates are of great interest as potential future therapeutics. Here we asked whether a small peptide, composed of five amino acids (5MER peptide) that was derived from the human pro-inflammatory CD44, could protect model nematodes from the toxicity of aggregative proteins that underlie the development of neurodegenerative disorders in humans. We found that the 5MER peptide mitigates the toxicity that stems from both, the AD-causing Aβ peptide and a stretch of poly-glutamine that is accountable to the development of several disorders including HD, without affecting lifespan. This protection was dependent on the activity of the aging-regulating transcription factors and associated with enhanced Aβ and polyQ35-YFP aggregation. A transcriptomic analysis unveiled that the peptide modulates the expression of various genes including these which are known as protein homeostasis (proteostasis) regulators such as txt-13, and modifiers of proteasome activity. The knockdown of txt-13 protects worms from proteotoxicity to the same extent as the 5MER peptide, suggesting that the peptide activates the transcellular chaperone signaling to promote proteostasis. Together, our results propose that the 5MER peptide should be considered as a component of future therapeutic cocktails for the treatment of neurodegenerative maladies.

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Cathepsin B Promotes Aβ Proteotoxicity by Modulating Aging Regulating Mechanisms

Project description:Cathepsin B Promotes Aβ Proteotoxicity by Modulating Aging Regulating Mechanisms

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Effects of intracellular amyloid toxicity on the transcriptome of MC65 human nerve cells

Project description:Amyloid beta (Aβ) accumulates within neurons in the brains of early stage Alzheimer's disease (AD) patients. However, the mechanism underlying its potential toxicity remains unclear. To elucidate this, a transcriptomic study was carried out using a nerve cell model of toxic intracellular aggregation of Aβ. The neuroprotective compound CMS121 was included as a validating tool. It was found that intracellular Aβ induces profound changes in the omics landscape of nerve cells that are associated with a cancer-like metabolic reprogramming, the oxytosis/ferroptosis cell death program, and physiological alterations detrimental to mitochondrial function. Our findings have implications for the understanding of the basic biology of proteotoxicity, aging and AD as well as for the development of future therapeutic interventions designed to target the oxytosis/ferroptosis programmed cell death pathway in the AD brain.

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Young bone marrows transplantation rejuvenates immune cells, attenuate cerebral Aβ accumulation and related pathologies in Alzheimer’s disease model mouse

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2023-06-27 | GSE235527 | GEO

A Nucleolar Mechanism Suppresses Organismal Proteostasis by Modulating Signaling of the TGF-β/ERK Axis

Project description:The protein homeostasis (proteostasis) network encompasses a myriad of mechanisms that maintain the integrity of the proteome by controlling various biological functions, including protein folding and degradation. Alas, aging-associated decline in the efficiency of this network enables protein aggregation and consequently the development of late onset neurodegenerative disorders, such as Alzheimer’s disease (AD). Accordingly, the maintenance of proteostasis through late stages of life bears the promise to delay the emergence of these devastating diseases. Yet, the identification of proteostasis-regulators is needed to assess the feasibility of this approach. Here we report that knocking down the activity of the nucleolar FIB-1-NOL-56 complex, protects model nematodes from proteotoxicity of the AD-causing, Aβ peptide. This mechanism promotes proteostasis across tissues by modulating the activity of TGF-β signaling and by enhancing proteasome activity. Our findings point at new research avenues toward the development of proteostasis-promoting therapies for neurodegenerative maladies.

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