Caspase Activation and Caspase-Mediated Cleavage of APP Is Associated with Amyloid β-Protein-Induced Synapse Loss in Alzheimer’s Disease

Park, Goonho; Nhan, Hoang; Tyan, Sheue-Houy; Kawakatsu, Yusuke; Zhang, Carolyn; Navarro, Mario; Koo, Edward H.

doi:10.1016/j.celrep.2020.107839

Cited by 60 publications

(36 citation statements)

References 79 publications

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“…Many apoptosis pathways have been linked to Aβ-induced cytotoxicity [ 57 , 58 ]. To examine, which apoptosis pathway is mainly associated with the vitamin K2-mediated protective effects, we used a number of different inhibitors targeted to a specific-signaling pathway.…”

Section: Resultsmentioning

confidence: 99%

Molecular Mechanism of Vitamin K2 Protection against Amyloid-β-Induced Cytotoxicity

2021

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The pathological role of vitamin K2 in Alzheimer’s disease (AD) involves a definite link between impaired cognitive functions and decreased serum vitamin K levels. Vitamin K2 supplementation may have a protective effect on AD. However, the mechanism underlying vitamin K2 protection has not been elucidated. With the amyloid-β (Aβ) cascade hypothesis, we constructed a clone containing the C-terminal fragment of amyloid precursor protein (β-CTF/APP), transfected in astroglioma C6 cells and used this cell model (β-CTF/C6) to study the protective effect of vitamin K2 against Aβ cytotoxicity. Both cellular and biochemical assays, including cell viability and reactive oxygen species (ROS), assays assay, and Western blot and caspase activity analyses, were used to characterize and unveil the protective role and mechanism of vitamin K2 protecting against Aβ-induced cytotoxicity. Vitamin K2 treatment dose-dependently decreased the death of neural cells. The protective effect of vitamin K2 could be abolished by adding warfarin, a vitamin K2 antagonist. The addition of vitamin K2 reduced the ROS formation and inhibited the caspase-3 mediated apoptosis induced by Aβ peptides, indicating that the mechanism underlying the vitamin K2 protection is likely against Aβ-mediated apoptosis. Inhibitor assay and Western blot analyses revealed that the possible mechanism of vitamin K2 protection against Aβ-mediated apoptosis might be via regulating phosphatidylinositol 3-kinase (PI3K) associated-signaling pathway and inhibiting caspase-3-mediated apoptosis. Our study demonstrates that vitamin K2 can protect neural cells against Aβ toxicity.

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Section: Resultsmentioning

confidence: 99%

Molecular Mechanism of Vitamin K2 Protection against Amyloid-β-Induced Cytotoxicity

2021

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“…This peptide has been suggested to be a toxic APP fragment, along with Ab, that could cause synaptic damage and neurodegeneration 1,7,9,10 . An inter-relationship among the activation of caspases, the intracellular C-terminal cleavage of APP, and Ab-induced toxicity towards amyloid pathology has been recently proposed 11 . But to date, it was not known that APP-C31 can directly interact with Ab and alter the folding behavior that ultimately leads to the Ab-related toxicity.…”

Section: Interactions Of App-c31 With Metals and Metal-ab And Its Impact On Metal-ab Aggregationmentioning

confidence: 99%

“…In AD-affected brains, the levels of activated caspases are elevated and give rise to caspasemediated APP fragments [6][7][8] . Like Ab, APP-C31 contributes to neuronal toxicity leading to apoptosis and synaptic depression 7,[9][10][11][12][13] . Mutation of APP from Asp664 to Ala that prevents the production of APP-C31 could diminish synaptic loss and neurodegeneration in AD transgenic mice 11,12 .…”

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confidence: 99%

“…Like Ab, APP-C31 contributes to neuronal toxicity leading to apoptosis and synaptic depression 7,[9][10][11][12][13] . Mutation of APP from Asp664 to Ala that prevents the production of APP-C31 could diminish synaptic loss and neurodegeneration in AD transgenic mice 11,12 . Thus, these findings imply that the amount of intracellular APP-C31 is augmented and, consequently, neurotoxicity is enhanced when AD develops.…”

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confidence: 99%

“…Recently, the co-localization of the C-terminal region of APP with Ab was observed in intraneuronal perinuclear compartments and multivesicular bodies in the brains of AD transgenic mice 14,15 . Moreover, studies with the Cterminal truncated APP, APP1-664, and mutant APP(Asp664Ala) suggested that Ab could activate caspases that induce the C-terminal cleavage of APP generating APP-C31 [11][12][13] . Despite these indications, the mechanism of how APP-C31 is involved in the pathology driven by Ab is not known to date.…”

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confidence: 99%

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APP-C31 Is an Intracellular Promoter of Amyloid-Beta Aggregation and Toxicity

Nam¹,

Park²,

Yan³

et al. 2021

Preprint

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Intracellular C-terminal cleavage of the amyloid precursor protein (APP) is elevated in the brain of Alzheimer’s disease (AD). Emerging evidence proposes a pathological relationship between the production of a C-terminal APP fragment, called APP-C31, and the toxicity induced by amyloid-beta (Abeta) that is a major contributor towards AD; however, the interaction between the two peptides and the consequent impact of APP-C31 on Abeta-related toxicity were unknown thus far. Here we report the discovery that APP-C31 facilitates the aggregation of Abeta and aggravates its toxicity at the intracellular level, with escalating neurodegeneration. APP-C31 forms a hetero-dimer with Abeta through the contacts onto the N-terminal and self-recognition regions of Abeta and induces its conformational transition accelerating amyloid fibrillization. APP-C31 promotes the perinuclear and intranuclear deposition of enlarged Abeta aggregates and, consequently, damages the nucleus leading to apoptosis. Abeta-induced degeneration of neurites in human neurons is also intensified by APP-C31. Our studies demonstrate a new function of APP-C31 as an intracellular factor of the proteopathy found in AD.

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APP‐C31: An Intracellular Promoter of Both Metal‐Free and Metal‐Bound Amyloid‐β₄₀ Aggregation and Toxicity in Alzheimer's Disease

Nam,

Lin,

Park

et al. 2023

Advanced Science

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Intracellular C‐terminal cleavage of the amyloid precursor protein (APP) is elevated in the brains of Alzheimer's disease (AD) patients and produces a peptide labeled APP‐C31 that is suspected to be involved in the pathology of AD. But details about the role of APP‐C31 in the development of the disease are not known. Here, this work reports that APP‐C31 directly interacts with the N‐terminal and self‐recognition regions of amyloid‐β40 (Aβ40) to form transient adducts, which facilitates the aggregation of both metal‐free and metal‐bound Aβ40 peptides and aggravates their toxicity. Specifically, APP‐C31 increases the perinuclear and intranuclear generation of large Aβ40 deposits and, consequently, damages the nucleus leading to apoptosis. The Aβ40‐induced degeneration of neurites and inflammation are also intensified by APP‐C31 in human neurons and murine brains. This study demonstrates a new function of APP‐C31 as an intracellular promoter of Aβ40 amyloidogenesis in both metal‐free and metal‐present environments, and may offer an interesting alternative target for developing treatments for AD that have not been considered thus far.

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Caspase Activation and Caspase-Mediated Cleavage of APP Is Associated with Amyloid β-Protein-Induced Synapse Loss in Alzheimer’s Disease

Abstract: Highlights d Ab-dependent caspase activation cleaves the APP C terminus, leading to synaptic injury d Inhibition of APP C-terminal cleavage ameliorates Ab-dependent synaptic injury d APP D664A mutation prevents APP C terminus cleavage and impairs caspase activation

Cited by 60 publications

References 79 publications

Molecular Mechanism of Vitamin K2 Protection against Amyloid-β-Induced Cytotoxicity

Molecular Mechanism of Vitamin K2 Protection against Amyloid-β-Induced Cytotoxicity

APP-C31 Is an Intracellular Promoter of Amyloid-Beta Aggregation and Toxicity

APP‐C31: An Intracellular Promoter of Both Metal‐Free and Metal‐Bound Amyloid‐β₄₀ Aggregation and Toxicity in Alzheimer's Disease

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Caspase Activation and Caspase-Mediated Cleavage of APP Is Associated with Amyloid β-Protein-Induced Synapse Loss in Alzheimer’s Disease

Abstract: Highlights d Ab-dependent caspase activation cleaves the APP C terminus, leading to synaptic injury d Inhibition of APP C-terminal cleavage ameliorates Ab-dependent synaptic injury d APP D664A mutation prevents APP C terminus cleavage and impairs caspase activation

Cited by 60 publications

References 79 publications

Molecular Mechanism of Vitamin K2 Protection against Amyloid-β-Induced Cytotoxicity

Molecular Mechanism of Vitamin K2 Protection against Amyloid-β-Induced Cytotoxicity

APP-C31 Is an Intracellular Promoter of Amyloid-Beta Aggregation and Toxicity

APP‐C31: An Intracellular Promoter of Both Metal‐Free and Metal‐Bound Amyloid‐β40 Aggregation and Toxicity in Alzheimer's Disease

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APP‐C31: An Intracellular Promoter of Both Metal‐Free and Metal‐Bound Amyloid‐β₄₀ Aggregation and Toxicity in Alzheimer's Disease