Secreted Amyloid Precursor Protein Alpha (sAPPα) Regulates the Cellular Proteome and Secretome of Mouse Primary Astrocytes

Abstract

Secreted amyloid precursor protein alpha (sAPPα), processed from a parent mammalian brain protein, amyloid precursor protein, can modulate learning and memory. Recently it has been shown to modulate the transcriptome and proteome of human neurons, including proteins with neurological functions. Here, we analysed whether the acute administration of sAPPα facilitated changes in the proteome and secretome of mouse primary astrocytes in culture. Astrocytes contribute to the neuronal processes of neurogenesis, synaptogenesis and synaptic plasticity. Cortical mouse astrocytes in culture were exposed to 1 nM sAPPα, and changes in both the whole-cell proteome (2 h) and the secretome (6 h) were identified with Sequential Window Acquisition of All Theoretical Fragment Ion Spectra–Mass Spectrometry (SWATH-MS). Differentially regulated proteins were identified in both the cellular proteome and secretome that are involved with neurologically related functions of the normal physiology of the brain and central nervous system. Groups of proteins have a relationship to APP and have roles in the modulation of cell morphology, vesicle dynamics and the myelin sheath. Some are related to pathways containing proteins whose genes have been previously implicated in Alzheimer’s disease (AD). The secretome is also enriched in proteins related to Insulin Growth Factor 2 (IGF2) signaling and the extracellular matrix (ECM). There is the promise that a more specific investigation of these proteins will help to understand the mechanisms of how sAPPα signaling affects memory formation.

Amyloid precursor protein induces reactive astrogliosis

“…Lack of changes in the transcriptomic profiles of astrocytes transfected with wildtype or familial APP mutations corroborates previous reports indicating that proteolytic processing of APP differs significantly between astrocytes and neurons 73–77 and suggests that full-length APP rather than its proteolytic fragments instigate reactive astrogliosis. Whether this is related to the dominance of the Ox-2 immunoglobulin- and Kunitz-type protease inhibitor domains-containing 770 amino acid long APP isoform 31,38,78–80 , which is enriched in astrocytes in AD 81,82 , remains to be investigated.…”

Amyloid precursor protein induces reactive astrogliosis

“…Favorably, despite all of these possible pitfalls, our efforts to perform experiments rigorously produced results that are largely aligned with previous work about APP in astrocytes. 37,39,44 Lack of in the transcriptomic profiles of astrocytes transfected with wildtype or familial APP mutations corroborates previous reports indicating that proteolytic processing of APP differs between astrocytes and neurons [74][75][76][77][78] and suggests that full-length APP rather than its proteolytic fragments instigate reactive astrogliosis. Whether this is related to the dominance of the Ox-2 immunoglobulin-and Kunitz-type protease inhibitor domains-containing 770 amino acid long APP isoform, 31,38,[79][80][81] which is enriched in astrocytes in AD, 82,83 remains to be investigated.…”

A pilot study on the immune cell proteome of long COVID patients shows changes to physiological pathways similar to those in myalgic encephalomyelitis/chronic fatigue syndrome

“…The fold change decision for inclusion may vary according to the biological system (cell or human patients) and whether such a fold change is likely to affect the biology—particularly relevant for human studies. A fold change minimum of 1.5 was selected here based on our previously published proteomic studies on samples from human patients and human neural and mammalian neural cells 29 , 38 , 39 . This inclusion limit returned enough proteins to perform a network analysis on proteins of interest biologically.…”