Abstract
Perturbation of lipid metabolism favours progression of Alzheimer disease, in which processing of Amyloid Precursor Protein (APP) has important implications. APP cleavage is tightly regulated by cholesterol and APP fragments regulate lipid homeostasis. Here, we investigated whether up or down regulation of full-length APP expression affected neuronal lipid metabolism. Expression of APP decreased HMG-CoA reductase (HMGCR)-mediated cholesterol biosynthesis and SREBP mRNA levels, while its down regulation had opposite effects. APP and SREBP1 co-immunoprecipitated and co-localized in the Golgi. This interaction prevented Site-2 protease-mediated processing of SREBP1, leading to inhibition of transcription of its target genes. A GXXXG motif in APP sequence was critical for regulation of HMGCR expression. In astrocytes, APP and SREBP1 did not interact nor did APP affect cholesterol biosynthesis. Neuronal expression of APP decreased both HMGCR and cholesterol 24-hydroxylase mRNA levels and consequently cholesterol turnover, leading to inhibition of neuronal activity, which was rescued by geranylgeraniol, generated in the mevalonate pathway, in both APP expressing and mevastatin treated neurons. We conclude that APP controls cholesterol turnover needed for neuronal activity.
Highlights
Processing of amyloid precursor protein (APP) by b- and g-secretase activities produces b-amyloid (Ab) peptide, which accumulates in extracellular senile plaques present in brain of patients with Alzheimer disease (AD)
Since the intracellular domain of Amyloid Precursor Protein (APP) (AICD) is a transcriptional regulator, we studied whether it could account for APP-dependent repression of HMG-CoA reductase (HMGCR) gene transcription
Our findings demonstrate that expression of APP at moderate levels in rat cortical neurons decreases cholesterol biosynthesis as well as mRNA levels of several genes involved in cholesterol homeostasis, namely the three sterol regulatory element binding proteins (SREBPs) isoforms SREBP1a, SREBP1c, SREBP2, as well as HMGCR, HMG-CoA synthase (HMGCS) and low density lipoprotein receptor (LDLR), which are three SREBP target genes
Summary
Processing of amyloid precursor protein (APP) by b- and g-secretase activities produces b-amyloid (Ab) peptide, which accumulates in extracellular senile plaques present in brain of patients with Alzheimer disease (AD). The main lipoproteins in brain are ApoE and clusterin, and ABCA7 is involved in lipids efflux from cells to lipoproteins. The identification of these susceptibility loci ß 2013 The Authors.
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