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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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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

Project description:Immunesenescence contributes to systematic aging and participates in the pathogenesis of Alzheimer’s disease (AD). To define the potential of immune rejuvenation in AD therapy, we reconstituted the immune systems of aged APP/PS1 mice through bone marrow transplantation (BMT). Single cell RNA sequencing (ScRNA-seq) of peripheral blood mononuclear cells (PBMCs) indicated that young BMT reverse the expression of aging- and AD-related genes in multiple cell types of PBMCs. Plasma proteome profiling also indicated the reduction of the plasma level of senescence-associated secretory phenotype (SASP) proteins after young BMT. Young BMT significantly reduced central and peripheral Aβ levels, alleviated brain Aβ plaque burden, neuronal degeneration, neuroinflammation, and behavioral deficits in the aged APP/PS1 mice. These effects occurred with the improved Aβ capacity of peripheral monocytes. Collectively, our study demonstrated that rejuvenation of immune system could decrease brain Aβ deposition and other AD-type pathologies, representing a potential therapeutic approach for AD.

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.

2024-10-02 | GSE247737 | GEO

Increased neutrophils in inflammatory bowel disease accelerate the accumulation of amyloid plaques in the mouse model of Alzheimer's disease

Project description:Alzheimer's disease (AD) is one of the neurodegenerative diseases and characterized by the appearance and accumulation of amyloid-β (Aβ) aggregates and phosphorylated tau with aging. We performed scRNAseq of immene cells in the brain from WT and AD mice.

2022-12-01 | GSE214747 | GEO

Non-Transgenic Guinea Pig Strains Exhibit Hallmarks of Human Brain Aging and Alzheimer’s Disease

Project description:Older age is the primary risk factor for most chronic diseases, including Alzheimer’s disease (AD). Current preclinical models to study brain aging and AD are mainly transgenic and harbor mutations intended to mirror brain pathologies associated with human brain aging/AD (e.g., by increasing production of amyloid precursor protein, amyloid beta [Aβ], and/or phosphorylated tau, all of which are key pathological mediators of AD). Although these models may provide insight on pathophysiological processes in AD, none completely recapitulate the disease and its strong age-dependence, and there has been limited success in translating preclinical results and treatments to humans. Here, we describe two non-transgenic guinea pig (GP) models, a standard PigmEnTed (PET) strain and lesser-studied Dunkin-Hartley (DH) strain, that may naturally mimic key features of brain aging and AD in humans. We show that brain aging in PET GP is transcriptomically similar to human brain aging, whereas older DH brains are transcriptomically more similar to human AD. Both strains/models also exhibit increased neurofilament light chain (NFL, a marker of neuronal damage) with aging, and DH animals display greater S100 calcium-binding protein B (S100β), ionized calcium-binding adapter molecule 1 (Iba1), and Aβ and phosphorylated tau— which are all important markers of neuroinflammation-associated AD. Collectively, our results suggest that both the PET and DH GP may be useful, non-transgenic models to study brain aging and AD, respectively.

2022-03-19 | GSE198736 | GEO

GM1 promotes early Aβ oligomer formation and maintenance

Project description:The aggregation of amyloid beta (Aβ) peptide is associated with Alzheimer’s disease (AD) pathogenesis. Cell membrane composition, especially monosialotetrahexosylganglioside (GM1), is known to promote the formation of Aβ fibrils, yet little is known about the roles of GM1 in the early steps of Aβ oligomer formation. Here, by using GM1-contained liposomes as a mimic of neuronal cell membrane, we demonstrate that GM1 is a critical trigger of Aβ oligomerization and aggregation. We find that GM1 not only promotes the formation of Aβ fibrils, but also facilitates the maintenance of Aβ oligomers on liposome membranes. We structurally characterize the Aβ oligomers formed on the membrane and find that GM1 captures Aβ by binding to its arginine-5 residue. To interrogate the mechanism of Aβ oligomer toxicity, we design a new liposome-based Ca2+-encapsulation assay and provide new evidence for the Aβ ion channel hypothesis. Finally, we conduct cell viability assay to determine the toxicity of Aβ oligomers formed on membranes. Overall, by uncovering the roles of GM1 in mediating early Aβ oligomer formation and maintenance, our work provides a novel direction for pharmaceutical research for AD.

2023-05-10 | PXD029117 | Pride

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