Pyroglutamate modification of ABeta-a pathogenic mechanism in Alzheimer's disease

• Autorzy: Rossner S.
• Języki publikacji: EN

Abstrakty

EN

N-terminally truncated and pyroglutamate (pGlu)-modified Abeta peptides (pGlu-Abeta) are major constituents of Abeta deposits in brains of Alzheimer’s disease (AD) patients. There is ample biochemical and cell biological evidence for the formation of pGluAbeta peptides by the enzymatic activity of glutaminyl euriti (QC). However, a thorough histopathological association between the spatial presence of QC and the formation of pGlu-Abeta deposits in human brain is still lacking. The role of QC in the formation of different types of pGlu-Abeta aggregates in neocortex and hippocampus of AD subjects was studied by immunohistochemistry. Live cell imaging and enzymatic activity assays were used to reveal secretion of QC from primary neurons. In many cases, there was a clear co-localization or spatial association between QC expressing neurons and pGlu-Abeta aggregates. Additionally, pGlu-Abeta aggregates were found to be present in brain regions with only few QC immunoreactive neurons. However, such brain regions are known to receive afferents from QC expressing neurons that are affected early by Abeta pathology in the course of the disease. This points towards a mechanism in which pGlu-Abeta and/or QC are being transported along euritis and released from synapses of projection neurons at their terminal fields. Indeed, live cell imaging and enzymatic activity assays demonstrated the secretion of QC from neurons in a constitutive and regulated manner. We conclude that pGlu-Abeta aggregates may develop through different mechanisms: intracellularly at sites of somatic QC activity as well as extracellularly through seeding at terminal fields of QC expressing projection neurons.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2015
• Tom: 75
• Numer: Supl.
• Opis fizyczny: p.S18-S19

Twórcy

autor

Rossner S.

• Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany