Molecular mechanism of Alzheimer's disease pathogenesis in Down Syndrome

Alzheimer's disease (AD) is the most common neurodegenerative disease leading to dementia. Neuritic plaques and neurofibrillary tangles are the two hallmarks of AD neuropathology. The molecular mechanism underlying AD pathogenesis remains unknown. It is believed that deposition of amyloid beta (Abeta) protein in the brain plays a pivotal role in AD pathogenesis. Abeta, the central component of neuritic plaques, is derived from beta-amyloid precursor protein (APP) by sequential cleavages by beta- and gamma-secretase. Nearly all individuals with Down Syndrome (DS) show characteristic AD pathological changes after their 30s. The molecular mechanism by which AD pathogenesis develops in DS patients is poorly defined. BACE1 is the major beta-secretase in vivo. BACE2 is the homolog of BACE1 and located on chromosome 21. In this study, we cloned and functionally characterized BACE2 gene promoter. Our studies show that the BACE2 gene promoter has a higher activity in non-neuronal cells while BACE1 promoter has a higher activity in neuronal cells. Although both can be activated by SP1, the transcription of BACE1 and BACE2 are distinctly regulated. Even though they are homologous in amino acid sequence, BACE1 and BACE2 cleave APP at distinct sites, leading to their opposing functions in AP production. N-terminal sequencing of BACE2 cleavage product shows that the cleavage site of BACE2 in APP is located between the 19th and 20th amino acid of Abeta. Thus, BACE2 is identified as a novel theta-secretase. Overexpression of BACE2 drastically decreases AP production in cells, whereas overexpression of BACE1 greatly increases Abeta production. We and others have shown that Abeta is elevated in brains of DS patients. Our study further shows that beta-secretase activity is abnormally increased. Further study reveals that BACE1 protein levels are markedly increased in DS fetal brain tissues. Time-lapse live imaging, cell fractionation, and pulse-chase experiments show that BACE1 accumulates abnormally in the Golgi of DS cells. These data demonstrate that abnormal BACE1 accumulation leads to elevated beta-secretase activity and subsequent Abeta deposition in DS patients. Our results provide a novel molecular mechanism by which AD develops in DS and suggest that inhibiting BACE1 or potentiating BACE2 would benefit AD patients.