Caspase-6 role in apoptosis of human neurons, amyloidogenesis, and Alzheimer's disease

Neuronal cell death, neurofibrillary tangles, and amyloid beta peptide (A b eta) deposition depict Alzheimer's disease (AD) pathology, but neuronal los s correlates best with dementia. We have shown that increased production of A beta is a consequence of neuronal apoptosis, suggesting that apoptosis a ctivates proteases involved in amyloid precursor protein (APP) processing, Here, we investigate key effecters of cell death, caspases, in human neuron al apoptosis and APP processing. We find that caspase-6 is activated and re sponsible for neuronal apoptosis by serum deprivation. Caspase-6 activity p recedes the time of commitment to neuronal apoptosis by 10 h, indicating po ssible activity without subsequent apoptosis, Inhibition of caspase-6 activ ity prevents serum deprivation-mediated increase of A beta. Caspase-6 direc tly cleaves APP at the C terminus and generates a C-terminal fragment of 3 kDa (Capp3) and an A beta-containing 6.5-kDa fragment, Capp6.5, that increa ses in serum-deprived neurons. A pulse-chase experiment reveals a precursor -product relationship between Capp6.5, intracellular A beta, and secreted A beta, indicating a potential alternate amyloidogenic pathway. Caspase-6 pr oenzyme is present in adult human brain tissue, and the p10 active caspase- 6 fragment is detected in AD brain tissue. These results indicate a possibl e alternate pathway for APP amyloidogenic processing in human neurons and a potential implication for this pathway in the neuronal demise of AD.