Mutations in amyloid precursor protein affect its interactions with presenilin/gamma-secretase

Topic: Brain proteins, microglia and lab models

Alzheimer's disease is characterized by accumulation of toxic beta-amyloid (Abeta) in the brain and neuronal death. Several mutations in presenilin (PS1) and beta-amyloid precursor protein (APP) associate with an increased Abeta(42/40) ratio. Abeta(42), a highly fibrillogenic species, is believed to drive Abeta aggregation. Factors shifting gamma-secretase cleavage of APP to produce Abeta(42) are unclear. We investigate the molecular mechanism underlying altered Abeta(42/40) ratios associated with APP mutations at codon 716 and 717. Using FRET-based fluorescence lifetime imaging to monitor APP-PS1 interactions, we show that I716F and V717I APP mutations increase the proportion of interacting molecules earlier in the secretory pathway, resulting in an increase in Abeta generation. A PS1 conformation assay reveals that, in the presence of mutant APP, PS1 adopts a conformation reminiscent of FAD-associated PS1 mutations, thus influencing APP binding to PS1/gamma-secretase. Mutant APP affects both intracellular location and efficiency of APP-PS1 interactions, thereby changing the Abeta(42/40) ratio.

@article{herl2009-19281847,
  author  = {Herl, L. and Thomas, A. V. and Lill, C. M. and Banks, M. and Deng, A. and Jones, P. B. and Spoelgen, R. and Hyman, B. T. and others},
  title   = {{Mutations in amyloid precursor protein affect its interactions with presenilin/gamma-secretase}},
  journal = {Molecular and cellular neurosciences},
  year    = {2009},
  doi     = {10.1016/j.mcn.2009.02.008},
  pmid    = {19281847},
  url     = {https://doi.org/10.1016/j.mcn.2009.02.008}
}

Key findings

• We investigate the molecular mechanism underlying altered Abeta(42/40) ratios associated with APP mutations at codon 716 and 717.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.mcn.2009.02.008
• PubMed: 19281847
• Original source →

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2 studies in the library carry the topic tag “mutations”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 2 tagged studies.

• A novel presenilin 2 mutation (V393M) in early-onset dementia with profound language impairment European journal of neurology · 2008-08-22 · usefulness score 41/100 · Biomarkers

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