Abstract
The amyloidogenic peptide, Aβ, provokes a series of events affecting distinct cellular pathways regulated by protein phosphorylation. Aβ inhibits protein phosphatases in a dose-dependent manner, thus it is expected that the phosphorylation state of specific proteins would be altered in response to Aβ. In fact several Alzheimer’s disease related proteins, such as APP and TAU, exhibit pathology associated hyperphosphorylated states. A systems biology approach was adopted and the phosphoproteome, of primary cortical neuronal cells exposed to Aβ, was evaluated. Phosphorylated proteins were recovered and those whose recovery increased or decreased, upon Aβ exposure across experimental sets, were identified. Significant differences were evident for 141 proteins and investigation of their interactors revealed key protein clusters responsive to Aβ treatment. Of these, 73 phosphorylated proteins increased and 68 decreased upon Aβ addition. These phosphorylated proteins represent an important resource of potential AD phospho biomarkers that should be further pursued.
Highlights
The Aβpeptide, derived by proteolytic cleavage[1,2] of the Alzheimer’s Amyloid Precursor Protein (APP), is associated with the onset of Alzheimer’s disease (AD)
The phosphorylation levels of many proteins involved in membrane trafficking changed, as is the case of ITSN1 whose phosphorylation levels increases in response to Aβ
ITSN1 has been implicated in Down’s syndrome and AD, possibly via c-JUN N terminal kinase activation[27]. It is a cytoplasmic membrane-associated protein involved in endocytic membrane traffic and appears to regulate the formation of clathrin-coated vesicles and to be involved in synaptic vesicle recycling
Summary
The Aβpeptide, derived by proteolytic cleavage[1,2] of the Alzheimer’s Amyloid Precursor Protein (APP), is associated with the onset of Alzheimer’s disease (AD). Protein phosphorylation is a key mechanism and regulates many cellular processes. Abnormal protein phosphorylation has been linked to numerous human diseases including AD. Both APP and TAU phosphorylation have been associated with this dementia[14,15]. It can activate Src family protein kinases, activate phosphatidylinositol. 3-kinase[18] and the cAMP response element-binding protein phosphorylation[19]. It is not surprising that Aβ prompts the production of NFTs via mediating the expression levels and/or activities of TAU protein kinases and phosphatases[21,25]. In the work described primary neuronal culture lysates were collected upon Aβexposure, enriched for phosphorylated proteins and the latter identified by mass spectrometry analysis. The proteins identified are strong biomarker candidates, and the networks presented reveal novel protein relationships and signalling cascades, relevant to unraveling the molecular basis of AD
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