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Alzheimers disease,characterized by formation of -amyloid plaque in patient brain,is closely associated with -secretase.Amyloid precursor protein(APP)is processed by -and -secretases in the extracellular space to produce a series of -amyloid peptides(A)exemplified by A 42 and A 40.Among all A s,A 42 is particularly prone to aggregation,resulting in formation of -amyloid plaque.The human -secretase is a membrane-embedded protease complex that comprises four components presenilin 1(PS1),Pen-2,Aph-1,and nicastrin.We previously determined two cryo-EM structures of human -secretase at 4.5 and 4.3(A)resolution.The first cryo-EM structure,determined in the presence of amphipols,allowed visualization of the intact human -secretase for the first time,with identification of 19 transmembrane segments(TMs)and a protease-like extracellular domain(ECD)from nicastrin [Lu et al,Nature 512,166-170(2014)].But the resolution range of EM densities in the transmembrane region was too low(5-7(A))to allow assignment of specific TMs to the four components.A subsequent crystal structure of eukaryotic nicastrin allowed improvement of the human nicastrin model and suggested an arrangement of the 19 TMs [Xie et al,PNAS 111,13349-13354(2014)].The second cryo-EM structure,with a resolution range of 4-5(A)in the transmembrane region,confirmed this arrangement by conclusively assigning all 20 TMs to the four components and revealed presence of one additional TM [Sun et al,PNAS,published online(2015)].Importantly,the second cryo-EM structure of human -secretase was solved in the detergent digitonin,thus eliminating the concern that the first structure might represent an artifact in harsh conditions.In this presentation,I will describe the first atomic structure of human -secretase at 3.4(A)resolution.This structure allows visualization of atomic details of all four components of human -secretase for the first time and reveals important functional insights.