A splice variant of beta-secretase deficient in the amyloidogenic processing of the amyloid precursor protein

beta -Secretase (BACE) initiates the amyloidogenic processing of the amyloi d precursor protein leading to the generation of the beta -amyloid, the mai n component of Alzheimer's disease senile plaques. BACE is a type I transme mbrane aspartyl protease of 501 amino acids. Here we describe a novel BACE mRNA lacking 132 base pairs that is expressed in the pancreas but not in th e brain. Sequence alignment indicates that the deleted fragment matches the terminal two-thirds of exon 3. The new BACE variant is short of a 44-amino acid region located between the two catalytic aspartyl residues. According ly, a 50-kDa form of BACE (BACE457) is detected in the human pancreas. When expressed in cells, BACE457 colocalizes with the marker for the endoplasmi c reticulum BiP. Moreover, BACE457 remains in a proenzymatic and endoglycos idase H-sensitive state, suggesting that its transport along the secretory pathway is blocked at the level of the endoplasmic reticulum. Notably, this novel form of BACE does not contribute to the processing of the amyloid pr ecursor protein. Our findings suggest that tissue-specific splicing of the BACE mRNA may explain the observation that in the human pancreas robust tra nscription of the BACE gene does not translate into recovered enzymatic act ivity.