Abstract
Alzheimer’s disease (AD) is the most common form of dementia globally and is characterized by aberrant accumulations of amyloid-beta (Aβ) and tau proteins. Oligomeric forms of these proteins are believed to be most relevant to disease progression, with oligomeric amyloid-β (oAβ) particularly implicated in AD. oAβ pathology spreads among interconnected brain regions, but how oAβ induces pathology in these previously unaffected neurons requires further study. Here, we use well characterized iPSC-derived human neurons to study the early changes to the proteome and phosphoproteome after 24 h exposure to oAβ 1-42. Using nLC-MS/MS and label-free quantification, we identified several proteins that are differentially regulated in response to acute oAβ challenge. At this early timepoint, oAβ induced the decrease of TDP-43, heterogeneous nuclear ribonucleoproteins (hnRNPs), and coatomer complex I (COPI) proteins. Conversely, increases were observed in 20 S proteasome subunits and vesicle associated proteins VAMP1/2, as well as the differential phosphorylation of tau at serine 208. These changes show that there are widespread alterations to the neuronal proteome within 24 h of oAβ uptake, including proteins previously not shown to be related to neurodegeneration. This study provides new targets for the further study of early mediators of AD pathogenesis.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia globally and is characterized by aberrant accumulations of amyloid-beta (Aβ) and tau proteins
In addition to changes in the proteome observed in the WT amyloid precursor protein (APP) neurons (AF22), we examined the effects of oligomeric amyloid-β (oAβ) stimulation on the proteome of iPSC-derived neurons from a donor harbouring the V717I London mutation (ADP2)
One of the most studied hallmarks of AD is the progressive propagation of Aβ pathology, thought to be caused by the spreading of oAβ among interconnected brain regions from neuron to neuron[5,22], further reviewed in[1,2,3,4]
Summary
Alzheimer’s disease (AD) is the most common form of dementia globally and is characterized by aberrant accumulations of amyloid-beta (Aβ) and tau proteins. We use well characterized iPSC-derived human neurons to study the early changes to the proteome and phosphoproteome after 24 h exposure to oAβ 1-42. Increases were observed in 20 S proteasome subunits and vesicle associated proteins VAMP1/2, as well as the differential phosphorylation of tau at serine 208 These changes show that there are widespread alterations to the neuronal proteome within 24 h of oAβ uptake, including proteins previously not shown to be related to neurodegeneration. In order to further our understanding of the acute effects of exposure to oAβ, we challenged human iPSC-derived neurons with oAβ for 24 h and examined the changes to the proteome and phosphoproteome elicited by this acute oAβ treatment. Others have shown the ability of oligomeric Aβ to bind tau and promote its fibrillization[11,12,13], indicating a close relationship between Aβ and tau in AD pathogenesis
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