Abstract
A growing body of evidence suggests a role for soluble alpha-amyloid precursor protein (sAPPalpha) in pathomechanisms of Alzheimer disease (AD). This cleavage product of APP was identified to have neurotrophic properties. However, it remained enigmatic what proteins, targeted by sAPPalpha, might be involved in such neuroprotective actions. Here, we used high-resolution two-dimensional polyacrylamide gel electrophoresis to analyze proteome changes downstream of sAPPalpha in neurons. We present evidence that sAPPalpha regulates expression and activity of CDK5, a kinase that plays an important role in AD pathology. We also identified the cytoprotective chaperone ORP150 to be induced by sAPPalpha as part of this protective response. Finally, we present functional evidence that the sAPPalpha receptor SORLA is essential to mediate such molecular functions of sAPPalpha in neurons.
Highlights
Amyloid precursor protein (APP) is a major etiologic agent in Alzheimer disease (AD)
We show that sAPPalpha regulates expression and activity of cyclin-dependent kinase 5 (CDK5), a kinase that plays an important role in AD pathology and that was previously shown to be activated by Abeta
We performed high-resolution 2-D electrophoresis (2-DE) combined with mass spectrometry to screen for proteins altered downstream of sAPPalpha signalling in neurons
Summary
Amyloid precursor protein (APP) is a major etiologic agent in Alzheimer disease (AD). Amyloidogenic processing of APP by beta- and gamma-secretases generates Amyloid-beta (Abeta), the main component of senile plaques. A growing body of evidence implicated another APP cleavage product, soluble alpha-APP (sAPPalpha), in AD pathology. This product is produced from APP by an alternative, non-amyloidogenic processing pathway and levels of sAPPalpha were shown to be reduced in the cerebrospinal fluid of humans with sporadic or familial AD [2,3,4]. Important evidence for a central function of sAPPalpha in the brain was provided by studies with mice deficient for APP and APLP2, an APP homolog with overlapping functions. Loss of sAPPalpha as observed in AD patients might contribute to disease pathology
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