Gamma Secretase-Activating Protein Is a Substrate for Caspase-3: Implications for Alzheimer’s Disease

Abstract

SUMMARY Background A major hallmark feature of Alzheimer’s disease (AD) is the accumulation of amyloid β (Aβ), whose formation is regulated by the γ-secretase complex and its activating protein (also known as GSAP). Because GSAP interacts with the γ-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 not known. Methods Post-mortem brain tissues 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 identify 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 demonstrate 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 since its pharmacological blockade reduces Aβ pathology in vivo. Interpretation Our data by identifying caspase-3 as the endogenous modulator of GSAP and Aβ production establish it as a novel, attractive and viable Aβ lowering therapeutic target for AD.

Frontal Cortex and Hippocampal γ-Secretase Activating Protein Levels in Prodromal Alzheimer Disease

“…The discrepancy in 16 kDa GSAP levels between DS and AD (present findings) could be related to the presence of an extra copy of the APP gene in DS that might stimulate the expression of GSAP or other confounding components such as transcription factors [9, 22]. Data indicate that formation of the 16 kDa GSAP active form depends on caspase-3 [9], an apoptotic marker that is elevated and highly expressed in neurofibrillary tangles and plaques, in both human AD and animal models of this disease [21]. Although previous investigations indicate that 16 kDa GSAP levels are associated with Aβ deposition [5, 6], here we found that GSAP protein levels did not correlate with amyloid and NFT scores either in the frontal cortex or hippocampus across clinical groups.…”

Glucose deprivation increases tau phosphorylation via P38 mitogen‐activated protein kinase

“…Cell immunostaining was carried out as previously described (Chu et al ., 2015). Briefly, after treatment, N2A‐APPswe cells were plated on glass coverslips, and the following day, fixed in 4% paraformaldehyde in PBS for 15 min at 22 °C.…”

Screening Indigenous Medicinal Plants of Northeast India for Their Anti-Alzheimer’s Properties

“…In spite of their excellent AChEinhibition capacity, the above drugs have serious side effects such as Nausea, vomiting, diarrhea, weight loss, loss of appetite and muscle weakness. 3,18 Many other plant compounds have shown remarkable AChE inhibitory capacity, for example, withanolides from Withania somnifera Dunal. (ashwaganda or Indian ginseng), cur cuminoids from Curcuma longa L., tanshinones from Salvia miltiorrhiza Bunge and quercetin from Quercus sp.…”

“…1,2 Because of the absence of a permanent cure, AD has become a major health problem, although there are some treatments that may slow down its advances. 3 It is estimated that there are 35.6 million people living with dementia worldwide and will increase to 65.7 million by 2030, whereby much of the increase will be in developing countries. 4 Neurofibrillary tangles, Amyloid plaques and loss of cholinergic neurons are three pathological findings commonly observed in the cerebral cortex of Alzheimer's disease cases.…”