Gamma secretase-activating protein is a substrate for caspase-3: Implications for Alzheimer's disease

Jin Chu, Jian Guo Li, Yash B. Joshi, Phillip F. Giannopoulos, Nicholas E. Hoffman, Muniswamy Madesh, Domenico Praticò

Producción científica: Articlerevisión exhaustiva

38 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Páginas (desde-hasta)720-728
Número de páginas9
PublicaciónBiological Psychiatry
Volumen77
N.º8
DOI
EstadoPublished - 2015
Publicado de forma externa

ASJC Scopus subject areas

  • Biological Psychiatry

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