Amyloid precursor protein modulates beta-catenin degradation.
BACKGROUND
The amyloid precursor protein (APP) is genetically associated with Alzheimer's disease (AD). Elucidating the function of APP should help understand AD pathogenesis and provide insights into therapeutic designs against this devastating neurodegenerative disease.


RESULTS
We demonstrate that APP expression in primary neurons induces beta-catenin phosphorylation at Ser33, Ser37, and Thr41 (S33/37/T41) residues, which is a prerequisite for beta-catenin ubiquitinylation and proteasomal degradation. APP-induced phosphorylation of beta-catenin resulted in the reduction of total beta-catenin levels, suggesting that APP expression promotes beta-catenin degradation. In contrast, treatment of neurons with APP siRNAs increased total beta-catenin levels and decreased beta-catenin phosphorylation at residues S33/37/T41. Further, beta-catenin was dramatically increased in hippocampal CA1 pyramidal cells from APP knockout animals. Acute expression of wild type APP or of familial AD APP mutants in primary neurons downregulated beta-catenin in membrane and cytosolic fractions, and did not appear to affect nuclear beta-catenin or beta-catenin-dependent transcription. Conversely, in APP knockout CA1 pyramidal cells, accumulation of beta-catenin was associated with the upregulation of cyclin D1, a downstream target of beta-catenin signaling. Together, these data establish that APP downregulates beta-catenin and suggest a role for APP in sustaining neuronal function by preventing cell cycle reactivation and maintaining synaptic integrity.


CONCLUSIONS
We have provided strong evidence that APP modulates beta-catenin degradation in vitro and in vivo. Future studies may investigate whether APP processing is necessary for beta-catenin downregulation, and determine if excessive APP expression contributes to AD pathogenesis through abnormal beta-catenin downregulation.
Chen
Yuzhi
Y
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. chenyuzhi@uams.edu
Bodles
Angela M
AM
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D015536:Down-Regulation / Q000502:physiology*; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D051176:beta Catenin