Synaptogenic effect of APP-Swedish mutation in familial Alzheimer's disease

Sci Transl Med. 2022 Oct 19;14(667):eabn9380. doi: 10.1126/scitranslmed.abn9380. Epub 2022 Oct 19.


Mutations in β-amyloid (Aβ) precursor protein (APP) cause familial Alzheimer's disease (AD) probably by enhancing Aβ peptides production from APP. An antibody targeting Aβ (aducanumab) was approved as an AD treatment; however, some Aβ antibodies have been reported to accelerate, instead of ameliorating, cognitive decline in individuals with AD. Using conditional APP mutations in human neurons for perfect isogenic controls and translational relevance, we found that the APP-Swedish mutation in familial AD increased synapse numbers and synaptic transmission, whereas the APP deletion decreased synapse numbers and synaptic transmission. Inhibition of BACE1, the protease that initiates Aβ production from APP, lowered synapse numbers, suppressed synaptic transmission in wild-type neurons, and occluded the phenotype of APP-Swedish-mutant neurons. Modest elevations of Aβ, conversely, elevated synapse numbers and synaptic transmission. Thus, the familial AD-linked APP-Swedish mutation under physiologically relevant conditions increased synaptic connectivity in human neurons via a modestly enhanced production of Aβ. These data are consistent with the relative inefficacy of BACE1 and anti-Aβ treatments in AD and the chronic nature of AD pathogenesis, suggesting that AD pathogenesis is not simply caused by overproduction of toxic Aβ but rather by a long-term effect of elevated Aβ concentrations.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease* / pathology
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism
  • Humans
  • Mutation / genetics
  • Sweden


  • Amyloid beta-Protein Precursor
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • APP protein, human