Mutant Presenilin 1 Increases the Expression and Activity of BACE1

Abstract

Mutations of the presenilin 1 (PS1) gene are the most common cause of early onset familial Alzheimer disease (FAD). PS1 mutations alter the activity of the ␥-secretase on the ␤-amyloid precursor protein (APP), leading to selective overproduction of ␤-amyloid (A␤) 42 peptides, the species that forms oligomers that may exert toxic effects on neurons. Here we show that PS1 mutations, expressed both transiently and stably, in non-neuronal and neuronal cell lines increase the expression and the activity of the ␤-secretase (BACE1), the rate-limiting step of A␤ production. Also, BACE1 expression and activity are elevated in brains of PS1 mutant knock-in mice compared with wild type littermates as well as in cerebral cortex of FAD cases bearing various PS1 mutations compared with in sporadic AD cases and controls. The up-regulation of BACE1 by PS1 mutations requires the ␥-secretase cleavage of APP and is proportional to the amount of secreted A␤42. A␤42, and not AICD (APP intracellular domain), is indeed the APP derivative that mediates the overexpression of BACE1. The effect of PS1 mutations on BACE1 may contribute to determine the wide clinical and pathological phenotype of early onset FAD.The ␤-amyloid peptide (A␤) 2 that accumulates in vulnerable brain regions in Alzheimer disease (AD) is released from the ␤-amyloid precursor protein (APP) by sequential cleavages by ␤-secretase and ␥-secretase. A single protein called BACE1 is responsible for ␤-secretase activity, whereas ␥-secretase involves at least four proteins including a catalytic subunit called presenilin-1 (PS1) (1, 2). Mutations of PS1 are the most common cause of early onset familial AD (FAD). The known effect of PS1 mutations on APP processing is the increased production of A␤ species ending at residue 42, which aggregates faster than the A␤40 isoform and accumulates in the brain in the state of soluble low molecular weight oligomers (3, 4). Small, soluble, and diffusible aggregates composed of a mixture of full-length and N-terminal-truncated A␤42 species appear early in the cerebral cortex of subjects at risk of Alzheimer disease pathology (5). The rate of accumulation as well as the properties of aggregation and toxicity of cerebral soluble A␤ depend on the ratio of the three major A␤ species, 1-42, pyroglutamate 3-42, and pyroglutamate 11-42 (6). We have shown that, in the cerebral cortex of FAD cases with mutations of PS1, the relative percentage of the two N-terminal-truncated A␤ species is significantly increased in comparison to sporadic AD cases (7). A relative increase of N-terminal-truncated A␤ peptides also occurs in the brain of transgenic mice bearing a double PS1 mutation (8). When overexpressed in cell lines, BACE1 increases the production of A␤ 11-x (9) and A␤ 3-x peptides (10) in vitro. BACE1 has been found to be transcriptionally regulated by several different mechanisms involving various transcription factors and pathways (11)(12)(13)(14)(15), and given the complexity and richness in transcription factor recognition sites of its gene p...

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