As people age they lose a small percentage of neurons in the brain without any clinical manifestation of memory loss.Accelerated neuronal loss in aging brains, however, leads to neurodegenerative diseases like Alzheimer's disease (AD).Epidemiological studies have unequivocally demonstrated that aging is the single most significant risk factor contributing to the development of AD, and identifying mechanisms to slow the aging process by preventing neuronal loss is one of the most dynamic research areas.Taking advantage of the well established vertebrate model, zebrafish, we examined the function of γ-secretase components that are responsible for the generation of amyloid g-protein, the key element of neuritic plaques found in brains of AD patients.We found that knockdown of a key factor, presenilin enhancer-2 (Pen-2), led to a reduction of neurons and axons.Neuronal loss in Pen-2 knockdown embryos is not due to a lack of neuronal precursor cells or cell proliferation.Instead, it was caused by massive apoptosis in the whole animal lacking Pen-2.Loss of neurons in Pen-2 knockdown embryos could be partially rescued by knockdown of tumor suppressor p53.The deletion analysis of truncated Pen-2 protein showed that its cytosolic loop is essential for protecting developing embryos from caspase-dependent apoptosis.In conclusion, acquisition of images directly from zebrafish living in 96 well plate allows us to visualize neuronal loss in genetically manipulated zebrafish and offers us the opportunity to screen thousands of vertebrate animals in real time.