Treatment of microglia with Anti-PrP monoclonal antibodies induces neuronal apoptosis in vitro

Adhikari, Utpal; Sakiz, Elif; Habiba, Umma; Mikhael, Meena; Senesi, Matteo; David, Monique; Guillemin, Gilles J.; Ooi, Lezanne; Karl, Tim; Collins, Steven J.; Tayebi, Mourad

doi:10.1016/j.heliyon.2021.e08644

Cited by 2 publications

(3 citation statements)

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“…It is well known that mitochondria are an important modulator of cell apoptosis through the release of cytochrome C and the resulting activation of the caspase signaling pathway ( Wang and Youle, 2009 ). PrP was also shown to modulate apoptosis in multiple conditions, exerting an anti-apoptotic role in neuronal and cancer cells ( Kim et al, 2004 ; Roucou et al, 2005 ; Gao et al, 2019 ; Adhikari et al, 2021 ). Therefore, it is plausible to suggest that the anti-apoptotic role of PrP may involve its interaction with mitochondrial lipid raft-like microdomains.…”

Section: Prion Association With Lipids In Physiologymentioning

confidence: 99%

What is the role of lipids in prion conversion and disease?

Conceição

Lemos

Barros

et al. 2023

Front. Mol. Neurosci.

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The molecular cause of transmissible spongiform encephalopathies (TSEs) involves the conversion of the cellular prion protein (PrPC) into its pathogenic form, called prion scrapie (PrPSc), which is prone to the formation of amorphous and amyloid aggregates found in TSE patients. Although the mechanisms of conversion of PrPC into PrPSc are not entirely understood, two key points are currently accepted: (i) PrPSc acts as a seed for the recruitment of native PrPC, inducing the latter’s conversion to PrPSc; and (ii) other biomolecules, such as DNA, RNA, or lipids, can act as cofactors, mediating the conversion from PrPC to PrPSc. Interestingly, PrPC is anchored by a glycosylphosphatidylinositol molecule in the outer cell membrane. Therefore, interactions with lipid membranes or alterations in the membranes themselves have been widely investigated as possible factors for conversion. Alone or in combination with RNA molecules, lipids can induce the formation of PrP in vitro-produced aggregates capable of infecting animal models. Here, we discuss the role of lipids in prion conversion and infectivity, highlighting the structural and cytotoxic aspects of lipid-prion interactions. Strikingly, disorders like Alzheimer’s and Parkinson’s disease also seem to be caused by changes in protein structure and share pathogenic mechanisms with TSEs. Thus, we posit that comprehending the process of PrP conversion is relevant to understanding critical events involved in a variety of neurodegenerative disorders and will contribute to developing future therapeutic strategies for these devastating conditions.

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Section: Prion Association With Lipids In Physiologymentioning

confidence: 99%

What is the role of lipids in prion conversion and disease?

Conceição

Lemos

Barros

et al. 2023

Front. Mol. Neurosci.

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“…It is believed that caspase-3 is a vital executor of apoptosis since it is either largely or completely responsible for the proteolytic cleavage of numerous important proteins (Adhikari et al, 2021b;Porter and Jänicke, 1999). Apoptosis may be initiated via different pathways, and in vivo studies in AD indicated that caspase 3-dependent pathway is activated (Banwait et al, 2008;Louneva et al, 2008).…”

Section: Treatment With Anti-aβ Antibodies Induces Caspase 3-dependen...mentioning

confidence: 99%

“…It is believed that caspase-3 is a vital executor of apoptosis since it is either largely or completely responsible for the proteolytic cleavage of numerous important proteins. 54,55 Apoptosis may be initiated via different pathways, and in vivo studies in AD indicated that caspase 3-dependent pathway is activated. 56,57 Pro-caspase-3 protein (32 kDa) is cleaved into 20, 19, or 17 kDa subunits, 58 therefore, we analyzed these active subunits by Western blotting (Figure 6).…”

Section: Treatment With Anti-aβ Antibodies Induces Caspase 3-dependen...mentioning

confidence: 99%

Therapeutic anti‐amyloid β antibodies cause neuronal disturbances

Adhikari

Khan

Mikhael

et al. 2022

Alzheimer's & Dementia

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Recent published clinical trial safety data showed that 41% of Alzheimer patients experienced amyloid-related imaging abnormalities (ARIA), marks of microhemorrhages and oedema in the brain, following administration of Biogen's Aduhelm/ aducanumab (amino acids 3-7 of the Aβ peptide). Similarly, Janssen/Pfizer's Bapineuzumab (amino acids 1-5 of the Aβ peptide) and Roche's Gantenerumab (amino acids 2-11/18-27 of the Aβ peptide) also displayed ARIA in clinical trials, including microhemorrhage and focal areas of inflammation or vasogenic oedema respectively. The molecular mechanisms underlying ARIA caused by therapeutic anti-Aβ antibodies remain largely unknown, however, recent reports demonstrated that therapeutic antiprion antibodies activate both neuronal apoptotic and allergenic proteomes following cross-linking cellular prion protein. Here, we report that treatment of human induced pluripotent stem cellsderived neurons (HSCN) from a non-demented donor, co-cultured with human primary microglia with anti-Aβ1-6, or anti-Aβ17-23 antibodies activate a significant number of both apoptotic and allergenic-related proteins as assessed by mass spectrometry. Interestingly, a large proportion of the identified proteins included cytokines such as IL-4, IL-12, and IL-13 suggesting a type-1 hypersensitivity response. Following flow cytometry analysis, several proinflammatory cytokines were significantly elevated following anti-Aβ1-6, or anti-Aβ17-23 antibody treatment. These results justify further and more robust investigation of the molecular mechanisms of ARIA during immunotherapy study trials of AD.

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Treatment of microglia with Anti-PrP monoclonal antibodies induces neuronal apoptosis in vitro

Abstract: Antibody cross-linking neuronal PrPC induces apoptosis. Antibody cross-linking microglial PrPC induces neuronal apoptosis. Different apoptotic pathways were triggered by specific anti-PrP antibody treatments.

Cited by 2 publications

References 152 publications

What is the role of lipids in prion conversion and disease?

What is the role of lipids in prion conversion and disease?

Therapeutic anti‐amyloid β antibodies cause neuronal disturbances

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