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Mutation of APP Caspase Cleavage Site at Position D664 Does Not Affect Dendritic Spine Morphology in Mice /

  • Author(s): Kawakatsu, Yusuke
  • et al.
Abstract

The amyloid cascade hypothesis posits that Alzheimer's disease (AD) is driven by the production of A[beta] from the cleavage of the amyloid precursor protein (APP) by secretases. However, APP is also cleaved by caspases to release a toxic peptide termed C31 into the cytoplasm that has been shown to increase cell death in vitro. A single point mutation from Asp to Ala at position 664 of APP (APP695 numbering scheme) prevents caspase cleavage of APP and attenuates A[beta]-induced toxicity, demonstrating a potential role for caspase cleavage of APP in Alzheimer's pathology. However, due to disadvantages such as APP overexpression and insertional artifacts in some transgenic lines, the protective effect of the D664A mutation remains unclear. We have developed a knock-in mouse line carrying the D664A mutation to study its effects on baseline dendritic morphology by crossing it with the GFP-M mouse. Immunofluorescent staining of DA/GFP -M brain sections revealed that the D664A mutation itself had no impact on the basal or apical dendritic spine morphology when compared to their WT/GFP-M littermates across different age groups. In a second study, primary hippocampal neuronal cultures from the DA mice and their WT littermates were treated with 7PA2 conditioned media (7PA2-CM) containing various A[beta]42 concentrations of to quantify the protective effect of this D664A mutation in dendritic spine density. However, our neuronal culture experiments failed to demonstrate any protective effects of the D664A mutation as it was retrospectively discovered that our 7PA2-CM lacked the A[beta]42 oligomers necessary to induce toxicity in WT controls

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