Media contributions
1Media contributions
Title Comment on Toward an AD CRISPR Therapy: Tweaking APP Terminus Cuts Plaque in Alzforum Degree of recognition International Media name/outlet Alzforum Country/Territory United States Date 27/06/2024 Description Aulston et al. provided compelling evidence that targeting the C-terminal coding region of amyloid precursor protein (APP) reduces its processing by β-secretase (BACE1). This reduction in BACE1 activity attenuates the amyloidogenic pathway and decreases the production of plaque-forming Aβ peptides. The study employed a CRISPR/Cas9 approach to target the sequence encoding the YENPTY motif, which interacts with BACE1. As the nucleotides encoding this motif are in the most 3' exon, the authors facilitated non-homologous end joining (NHEJ) using their CRISPR/Cas9 technique. This led to a truncated version of APP with reduced BACE1 interaction capacity. In vivo mouse models showed that not only BACE1 activity but also plaque load and neuroinflammation were reduced.
These intriguing results raise the question of whether the observed effects on glial cells are direct, or a consequence of reduced Aβ40 and Aβ42 production. Overall, this elegant study successfully reversed Alzheimer’s disease pathology related to Aβ in mouse models. However, translating these findings to humans poses challenges, including delivery methods and the presence of tau pathology. Investigating the impact of CRISPR/Cas9-mediated APP modifications on tau pathology in Alzheimer's disease would be highly relevant.URL https://www.alzforum.org/news/research-news/toward-ad-crispr-therapy-tweaking-app-terminus-cuts-plaque Persons Kristine Freude
Keywords
- Alzheimers
- CRISPR
- Gene therapy