Contradictory Roles of BACE1 and BACE2 in the Pathogenesis of Alzheimer’s Disease in Down Syndrome

摘要

The pathogenesis of Down syndrome remains unknown. Some genes triplicated in Down sy-ndromewere proposed to contribute to the pathogenesis of DS and also the developmen-tof AD in DS.Chromosome 21 contains about 367 genes，including APP and BACE2. The e-xtra copy of APP inDown syndrome probably contributes to AD pathogenesis in DS pati-ents. However，an APPexpression study in developmental and aging of Down syndrome s-howed that APP was detected infetuses and infants，the immunoreactivity disappearedfrom childhood to young adults and reappearedfrom late adults correlating with the a-ppearance of senile plaques. Thedisappearance of APP immunoreact-ivity in childhood and early adulthood cannot explain thecontinuous accumulation ofAPP in Down syndrome patients. Furthermore，the onset of AD variesgreatly in DS pati-ents，which cannot be explained by the 99% duplication of APP gene due to trisomyof chromosome 21. So we hypothesized that some other genes also contribute to the pathogenesis ofAlzheimer’s disease in DS patients. C99，the -secretase cleavage product of APP，and A werepredominantly increased in Down syndrome patients，suggesting the increase of secretase activityin spite of APP increase. As BACE2 is the homolog of BACE1 and located in the critical region of Down syndrome，the extra copy of BACE2 might therefore play a role inabnormal processing of APP in DS.