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APP Ser675 phosphorylation alters APP processing resulting in decreased secretion of neuroprotective ectodomain sAPPalpha
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.ORCID-id: 0000-0001-6461-451X
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.ORCID-id: 0000-0002-8268-3006
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.ORCID-id: 0000-0002-8630-2127
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of amyloid-β (Aβ) peptides. Aβ is a cleavage product of the amyloid precursor protein (APP) and aberrant post-translational modifications of APP could alter APP processing and increased Aβ generation. In AD brain, seven different residues, including Ser675 (APP695 numbering), in the APP cytoplasmic domain has been found to be phosphorylated. Here we for the first time show that phosphorylation of APP at Ser675 alters APP processing, without affecting the plasma membrane level of APP. The altered processing results in increased expression of an alternative CTF, similar in size to β-secretase generated C99, but sensitive to metalloprotease inhibitors. Moreover, reduced secretion of sAPPα, as well as total sAPP, was observed. Taken together these findings suggest that Ser675 phosphorylation likely promote APP processing by the metalloprotease Meprin β, an alternative β-secretase localized at the plasma membrane and known to generate a C99 like CTF, but no sAPP fragments. As previous studies have shown that the Meprin β CTF can be furthered processed by γ-secretase yielding highly aggregate prone, truncated Aβ peptides, an increased Meprin β processing of APP upon Ser675 phosphorylation could contribute to AD pathology. It will hence be of importance to clarify how APP Ser675 phosphorylation could promote Meprin β cleavage at the plasma membrane in future studies.

Nyckelord [en]
Alzheimer's disease, APP, Fe65
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
neurokemi med molekylär neurobiologi
Identifikatorer
URN: urn:nbn:se:su:diva-160320OAI: oai:DiVA.org:su-160320DiVA, id: diva2:1249099
Tillgänglig från: 2018-09-18 Skapad: 2018-09-18 Senast uppdaterad: 2019-12-17Bibliografiskt granskad
Ingår i avhandling
1. Phosphorylation regulates APP and Fe65, two key players in Alzheimer’s disease
Öppna denna publikation i ny flik eller fönster >>Phosphorylation regulates APP and Fe65, two key players in Alzheimer’s disease
2018 (Engelska)Licentiatavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Alzheimer’s disease (AD) is a slow progressive neurodegenerative disease characterized by the accumulation of toxic amyloid beta (Aβ) peptide within the brain. APP plays an important role in AD, as the Aβ is formed when APP is sequentially cleaved by β- and γ-secretase. This is known as amyloidogenic processing of APP. However, non-amyloidogenic processing, in which APP is cleaved by α-secretases in the middle of the Aβ sequence, giving rise to the neuroprotective fragment sAPPα is also possible. In addition to amyloidogenic and non-amyloidogenic processing, APP can be processed along non-canonical pathways by δ, η , capase or Meprin β, resulting in numerous fragments which may have different functional properties. In paper 1, we for the first time show that phosphorylation of APP at Ser675 alters APP processing resulting in a significant decrease in the release of total sAPP and sAPPα, without affecting the plasma membrane level of APP. We further show an increased level of a slower migrating APP-CTF, similar to the expected size of β-secretase generated C99-CTF. However, no expression of the major β-secretase BACE1 was found in the model used and in the presence of metalloprotease inhibitors, generation of the slower migrating CTF was blocked. Taken together these findings suggest that Ser675 phosphorylation might promote APP processing by the metalloprotease Meprin β, an alternative β-secretase localized at the plasma membrane. How Ser675 phosphorylation could promote Meprin β cleavage is unclear, but an altered APP protein interaction could be involved as we found that mutation of Ser675 increased APP interaction with the adaptor protein Fe65. In paper 2, we wanted to elucidate more about how Fe65 is regulated and found that phosphorylated forms of Fe65 preferentially localize to the cytoplasm. Furthermore we showed that the Fe65 PTB2 domain, rather than the WW domain, plays an important role in localizing Fe65 to the nucleus. Together our results show that phosphorylation regulates both APP and Fe65, two important proteins linked to AD.

Ort, förlag, år, upplaga, sidor
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2018
Nyckelord
Alzheimer's disease, APP, Fe65, phosphorylation, RIP
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
neurokemi med molekylär neurobiologi
Identifikatorer
urn:nbn:se:su:diva-160321 (URN)
Presentation
2018-10-19, C458, Heilbronnsalen, Svante Arrhenius väg 16, Stockholm, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2019-01-17 Skapad: 2018-09-18 Senast uppdaterad: 2019-01-17Bibliografiskt granskad

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Menon, PreetiKoistinen, NiinaStröm, Anna-Lena
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