TY - JOUR
T1 - Gamma secretase-activating protein is a substrate for caspase-3
T2 - Implications for Alzheimer's disease
AU - Chu, Jin
AU - Li, Jian Guo
AU - Joshi, Yash B.
AU - Giannopoulos, Phillip F.
AU - Hoffman, Nicholas E.
AU - Madesh, Muniswamy
AU - Praticò, Domenico
N1 - Publisher Copyright:
© 2015 Society of Biological Psychiatry.
PY - 2015
Y1 - 2015
N2 - BACKGROUND: A major feature of Alzheimer's disease (AD) is the accumulation of amyloid-beta (Aβ), whose formation is regulated by the gamma-secretase complex and its activating protein (also known as GSAP). Because GSAP interacts with gamma-secretase without affecting the cleavage of Notch, it is an ideal target for a viable anti-Aβ therapy. However, despite much interest in this protein, the mechanisms involved in its neurobiology are unknown. METHODS: Postmortem brain tissue samples from AD patients, transgenic mouse models of AD, and neuronal cells were used to investigate the molecular mechanism involved in GSAP formation and subsequent amyloidogenesis. RESULTS: We identified a caspase-3 processing domain in the GSAP sequence and provide experimental evidence that this caspase is essential for GSAP activation and biogenesis of Aβ peptides. Furthermore, we demonstrated that caspase-3-dependent GSAP formation occurs in brains of individuals with AD and two different mouse models of AD and that the process is biologically relevant because its pharmacological blockade reduces Aβ pathology in vivo. CONCLUSIONS: Our data, by identifying caspase-3 as the endogenous modulator of GSAP and Aβ production, establish caspase-3 as a novel, attractive and viable Aβ-lowering therapeutic target for AD.
AB - BACKGROUND: A major feature of Alzheimer's disease (AD) is the accumulation of amyloid-beta (Aβ), whose formation is regulated by the gamma-secretase complex and its activating protein (also known as GSAP). Because GSAP interacts with gamma-secretase without affecting the cleavage of Notch, it is an ideal target for a viable anti-Aβ therapy. However, despite much interest in this protein, the mechanisms involved in its neurobiology are unknown. METHODS: Postmortem brain tissue samples from AD patients, transgenic mouse models of AD, and neuronal cells were used to investigate the molecular mechanism involved in GSAP formation and subsequent amyloidogenesis. RESULTS: We identified a caspase-3 processing domain in the GSAP sequence and provide experimental evidence that this caspase is essential for GSAP activation and biogenesis of Aβ peptides. Furthermore, we demonstrated that caspase-3-dependent GSAP formation occurs in brains of individuals with AD and two different mouse models of AD and that the process is biologically relevant because its pharmacological blockade reduces Aβ pathology in vivo. CONCLUSIONS: Our data, by identifying caspase-3 as the endogenous modulator of GSAP and Aβ production, establish caspase-3 as a novel, attractive and viable Aβ-lowering therapeutic target for AD.
KW - Alzheimer's disease
KW - Amyloid beta
KW - Caspase-3
KW - Gamma secretase
KW - Gamma secretase-activating protein
KW - Transgenic mice
UR - http://www.scopus.com/inward/record.url?scp=84933279721&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84933279721&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2014.06.003
DO - 10.1016/j.biopsych.2014.06.003
M3 - Article
C2 - 25052851
AN - SCOPUS:84933279721
SN - 0006-3223
VL - 77
SP - 720
EP - 728
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 8
ER -