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

Abstract Neuronal cell death, neurofibrillary tangles, and amyloid β peptide (Aβ) deposition depict Alzheimer’s disease (AD) pathology, but neuronal loss correlates best with dementia. We have shown that increased production of Aβ is a consequence of neuronal apoptosis, suggesting that apoptosis activates proteases involved in amyloid precursor protein (APP) processing. Here, we investigate key effectors of cell death, caspases, in human neuronal apoptosis and APP processing. We find that caspase-6 is activated and responsible for neuronal apoptosis by serum deprivation. Caspase-6 activity precedes the time of commitment to neuronal apoptosis by 10 h, indicating possible activity without subsequent apoptosis. Inhibition of caspase-6 activity prevents serum deprivation-mediated increase of Aβ. Caspase-6 directly cleaves APP at the C terminus and generates a C-terminal fragment of 3 kDa (Capp3) and an Aβ-containing 6.5-kDa fragment, Capp6.5, that increases in serum-deprived neurons. A pulse-chase experiment reveals a precursor-product relationship between Capp6.5, intracellular Aβ, and secreted Aβ, indicating a potential alternate amyloidogenic pathway. Caspase-6 proenzyme is present in adult human brain tissue, and the p10 active caspase-6 fragment is detected in AD brain tissue. These results indicate a possible alternate pathway for APP amyloidogenic processing in human neurons and a potential implication for this pathway in the neuronal demise of AD.