Journal Article

DZNE-2020-05622

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Posttranslational modification impact on the mechanism by which amyloid-β induces synaptic dysfunction.

Grochowska, K. M. ; Yuanxiang, P. ; Bär, J. ; Raman, R. ; Brugal, G. ; Sahu, G. ; Schweizer, M. ; Bikbaev, A. ; Schilling, S. ; Demuth, H.-U. ; Kreutz, M. R. (Last author)DZNE*

2017
Wiley Hoboken, NJ [u.a.]

This record in other databases:    

Please use a persistent id in citations: doi:10.15252/embr.201643519

Abstract: Oligomeric amyloid-β (Aβ) 1-42 disrupts synaptic function at an early stage of Alzheimer's disease (AD). Multiple posttranslational modifications of Aβ have been identified, among which N-terminally truncated forms are the most abundant. It is not clear, however, whether modified species can induce synaptic dysfunction on their own and how altered biochemical properties can contribute to the synaptotoxic mechanisms. Here, we show that a prominent isoform, pyroglutamated Aβ3(pE)-42, induces synaptic dysfunction to a similar extent like Aβ1-42 but by clearly different mechanisms. In contrast to Aβ1-42, Aβ3(pE)-42 does not directly associate with synaptic membranes or the prion protein but is instead taken up by astrocytes and potently induces glial release of the proinflammatory cytokine TNFα. Moreover, Aβ3(pE)-42-induced synaptic dysfunction is not related to NMDAR signalling and Aβ3(pE)-42-induced impairment of synaptic plasticity cannot be rescued by D1-agonists. Collectively, the data point to a scenario where neuroinflammatory processes together with direct synaptotoxic effects are caused by posttranslational modification of soluble oligomeric Aβ and contribute synergistically to the onset of synaptic dysfunction in AD.

Keyword(s): Alzheimer Disease: physiopathology (MeSH) ; Amyloid beta-Peptides: genetics (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Animals (MeSH) ; Mice (MeSH) ; Nerve Tissue Proteins: metabolism (MeSH) ; Neuroimmunomodulation (MeSH) ; Neuronal Plasticity (MeSH) ; Peptide Fragments: genetics (MeSH) ; Peptide Fragments: metabolism (MeSH) ; Protein Isoforms (MeSH) ; Protein Processing, Post-Translational (MeSH) ; Receptors, N-Methyl-D-Aspartate: metabolism (MeSH) ; Signal Transduction (MeSH) ; Synapses: metabolism (MeSH) ; Synapses: physiology (MeSH) ; Tumor Necrosis Factor-alpha: biosynthesis (MeSH) ; Amyloid beta-Peptides ; Jacob protein, mouse ; Nerve Tissue Proteins ; Peptide Fragments ; Protein Isoforms ; Receptors, N-Methyl-D-Aspartate ; Tumor Necrosis Factor-alpha ; amyloid beta-protein (3-42), pyroglutamyl(3)-

---

Contributing Institute(s):

1. U Preclinical Researchers T2 - Magdeburg (U Preclinical Researchers T2 - Magdeburg)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2017

---

Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; IF >= 5 ; JCR ; SCOPUS ; Web of Science Core Collection

---