Aη-α and Aη-β peptides impair LTP ex vivo within the low nanomolar range and impact neuronal activity in vivo

Mensch, Maria; Dunot, Jade; Yishan, Sandy M; Harris, Sam; Blistein, Aline; Avdiu, Alban; Pousinha, Paula A.; Giudici, Camilla; Busche, Marc Aurel; Jedlicka, Paul; Willem, Michael; Marie, Hélène

doi:10.1186/s13195-021-00860-1

Cited by 10 publications

(8 citation statements)

References 28 publications

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“…The physiological relevance of the APP processing pathway leading to Aη peptides remains unclear. Due to the higher abundance of Aη peptides in the brain than the well-established Aβ peptides (Willem et al ., 2015) and their potential involvement in impairing long-term potentiation (LTP) (Mensch et al ., 2021), it is intriguing to speculate that this non-canonical APP processing pathway may be implicated in Alzheimer’s disease. It is therefore necessary to investigate the in vivo relevance of these pathways to understand their potential involvement in Alzheimer’s disease.…”

Section: Discussionmentioning

confidence: 99%

“…Following MT5-MMP cleavage, α- or β-secretase would cleave the membrane bound C-terminal fragment and generate Aη fragments (Aη-α or Aη-β, respectively), and MT5-MMP was accordingly named η-secretase (Willem et al ., 2015). Aη peptides impair long-term potentiation and strikingly, are about five times more abundant than Aβ peptides in human brain (Mensch et al , 2021; Willem et al ., 2015). An Alzheimer’s disease mouse model (5xFAD) deficient for MT5-MMP showed reduced Aβ formation and maintained learning by promoting enhanced trafficking of APP to the endo-lysosomal compartment (Baranger et al , 2016a; Baranger et al , 2016b; Garcia-Gonzalez et al , 2021).…”

Section: Introductionmentioning

confidence: 99%

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Eta-secretase-like processing of the amyloid precursor protein (APP) by RHBDL4

Ylauna Christine Megane,

Paschkowsky,

Recinto

et al. 2023

Preprint

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The amyloid precursor protein (APP) has been extensively studied with regards to its contribution to the pathology of Alzheimer's disease. APP is an ubiquitously expressed type I transmembrane protein synthesized in the endoplasmic reticulum (ER) and translocated to the plasma membrane where it undergoes proteolytic cleavages by several identified proteases. Conversely to other known proteases, we previously elucidated human rhomboid protease RHBDL4 as a novel APP processing enzyme where several cleavages likely occur already in the ER. Interestingly, the pattern of RHBDL4-derived large APP C-terminal fragments resemble those generated by the η-secretase or MT5-MMP, which was described to generate so called Aη fragments. The similarity in large APP C-terminal fragments between both proteases raised the question whether RHBDL4 may contribute to η-secretase activity and Aη-like fragments. Here, we identified two cleavage sites of RHBDL4 in APP by mass spectrometry, which, intriguingly, lie in close proximity to the cleavage sites of MT5-MMP. Indeed, we observed that RHBDL4 generates Aη-like fragments in vitro without contributions of α-, β-, or γ-secretases. Such Aη-like fragments are likely generated in the ER since RHBDL4-derived APP-C-terminal fragments do not reach the cell surface. Inherited, familial APP mutations appear to not affect this processing pathway. In RHBDL4 knockout mice, we observed increased cerebral full length APP levels in comparison to WT brains in support of RHBDL4 being a physiologically relevant protease for APP. Furthermore, we found secreted Aη fragments in dissociated mixed cortical cultures from wild type mice, however significantly less Aη fragments in cultures from RHBDL4 knockout mice. Our data underscores that RHBDL4 contributes to η-secretease-like processing of APP and that RHBDL4 is a physiologically relevant protease for APP.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Eta-secretase-like processing of the amyloid precursor protein (APP) by RHBDL4

Ylauna Christine Megane,

Paschkowsky,

Recinto

et al. 2023

Preprint

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“…In addition, exosomes released from neurons have been described to regulate synaptic activity 45 . Further, hCTF yields Aha and Ahb, the influence of which on hippocampal long-term potentiation has led to discrepant conclusions 7,46 . Apparently, Aηa and Aηb peptides could impair synaptic activity 46 .…”

Section: Discussionmentioning

confidence: 99%

“…Further, hCTF yields Aha and Ahb, the influence of which on hippocampal long-term potentiation has led to discrepant conclusions 7,46 . Apparently, Aηa and Aηb peptides could impair synaptic activity 46 . This adds support to the conclusion that hCTF directly per se, or indirectly, as a precursor, could well contribute to AD pathology.…”

Section: Discussionmentioning

confidence: 99%

The η-secretase-derived APP fragment ηCTF is localized in Golgi, endosomes and extracellular vesicles and contributes to Aβ production

Afram

Lauritzen

Bourgeois

et al. 2023

Cell. Mol. Life Sci.

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The processing of the amyloid precursor protein (APP) is one of the key events contributing to Alzheimer’s disease (AD) etiology. Canonical cleavages by β- and γ-secretases lead to Aβ production which accumulate in amyloid plaques. Recently, the matrix metalloprotease MT5-MMP, referred to as η-secretase, has been identified as a novel APP cleaving enzyme producing a transmembrane fragment, ηCTF that undergoes subsequent cleavages by α- and β-secretases yielding the Aηα and Aηβ peptides, respectively. The functions and contributions of ηCTF and its related fragments to AD pathology are poorly understood. In this study, we designed a novel immunological probe referred to as ηCTF-NTer antibody that specifically interacts with the N-terminal part of ηCTF targeting ηCTF, Aηα, Aηβ but not C99, C83 and Aβ. We examined the fate and localization of ηCTF fragment in various cell models and in mice. We found that overexpressed ηCTF undergoes degradation in the proteasomal and autophagic pathways and accumulates mainly in the Golgi and in endosomes. Moreover, we observed the presence of ηCTF in small extracellular vesicles purified from neuroblastoma cells or from mouse brains expressing ηCTF. Importantly, the expression of ηCTF in fibroblasts devoid on APP leads to Aβ production demonstrating its contribution to the amyloidogenic pathway. Finally, we observed an ηCTF-like immunoreactivity around amyloid plaques and an age-dependent accumulation of ηCTF in the triple-transgenic mouse AD model. Thus, our study suggests that the ηCTF fragment likely contributes to AD pathology by its exosomal spreading and involvement in Aβ production.

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“…These mouse models also exhibit epileptic activity on EEG, are more susceptible to evoked seizures, and can even have spontaneous seizures ( Ziyatdinova et al, 2011 ; Sanchez et al, 2012 ; Johnson et al, 2020 ; Vande Vyver et al, 2022 ). Whether it is APP or one of its breakdown products that causes this increased neuronal activity and seizure phenotype in genetic mouse models of AD is still subject to debate, although the main suspect is Aβ ( Vogt et al, 2011 ; Born et al, 2014 ; Mensch et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

The intracerebral injection of Aβ1-42 oligomers does not invariably alter seizure susceptibility in mice

Vande Vyver,

Daeninck,

De Smet

et al. 2023

Front. Aging Neurosci.

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ObjectivesEpileptiform activity and seizures are present in patients with Alzheimer’s disease (AD) and genetic animal models of AD. Amyloid beta 1-42 (Aβ1-42) oligomers are thought to be crucial in AD and can cause neuronal hyperexcitability in vitro. However, it is unclear whether these Aβ1-42 oligomers cause the increased seizure susceptibility in vivo in people with AD and in AD animal models, nor via which mechanisms it would do so. We investigated this question by injecting Aβ1-42 oligomers intracerebrally in mice and assessed its impact on seizure susceptibility.Materials and methodsWe performed a single intracerebral injection of synthetic Aβ1-42 oligomers or scrambled Aβ1-42 in NMRI mice in three different cohorts and subjected them to an i.v. infusion of a chemoconvulsant. We evoked the seizures 1.5 h, 1 week, or 3 weeks after the intracerebral injection of Aβ1-42 oligomers, covering also the timepoints and injection locations that were used by others in similar experimental set-ups.ResultsWith a thioflavine T assay and transmission electron microscopy we confirmed that Aβ1-42 monomers spontaneously aggregated to oligomers. We did not find an effect of Aβ1-42 oligomers on susceptibility to seizures – evoked 1.5 h, 1 week or 3 weeks – after their intracerebral injection.SignificanceThe lack of effect of Aβ1-42 oligomers on seizure susceptibility in our experiments contrasts with recent findings in similar experimental set-ups. Contradicting conclusions are frequent in experiments with Aβ1-42 and they are often attributed to subtle differences in the various aggregation forms of the Aβ1-42 used in different experiments. We confirmed the presence of Aβ1-42 oligomers with state-of-the-art methods but cannot ascertain that the protein aggregates we used are identical to those used by others. Whether our findings or those previously published best represent the role of Aβ1-42 oligomers on seizures in AD remains unclear.

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Aη-α and Aη-β peptides impair LTP ex vivo within the low nanomolar range and impact neuronal activity in vivo

Cited by 10 publications

References 28 publications

Eta-secretase-like processing of the amyloid precursor protein (APP) by RHBDL4

Eta-secretase-like processing of the amyloid precursor protein (APP) by RHBDL4

The η-secretase-derived APP fragment ηCTF is localized in Golgi, endosomes and extracellular vesicles and contributes to Aβ production

The intracerebral injection of Aβ1-42 oligomers does not invariably alter seizure susceptibility in mice

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