[The precursor of amyloid peptide in Alzheimer disease: a protein with multiple functions].

Abstract

Cellular metabolism of the amyloid precursor protein (APP) has been widely studied, but the function of the protein remains elusive. APP knock out mice do not show any phenotype, due to in vivo compensation by APLP genes, encoding proteins similar to APP. In order to study the neuronal metabolism of APP, human APP has been expressed in rat cortical neurons in culture. Following differentiation in culture, rat cortical neurons are organized into networks of connected cells, which show neuronal activity in the form of spontaneous and synchronous calcium oscillations. Expression of human APP in these neuronal networks inhibits calcium oscillations, while downregulation of endogenous APP expression increases the frequency and decreases the amplitude of oscillations. Therefore, APP controls neuronal calcium homeostasis and excitability. In the same experimental model, APP is also able to control the neuronal synthesis of cholesterol. Finally, the APP carboxy terminal domain is involved in the epigenetic control of gene expression. Modulation of neuronal expression of APP allows to identify several important functions of the precursor of the amyloid peptide found in senile plaques of Alzheimer disease.