Thomas Sudhof, Postdoctoral Faculty Sponsor
Synaptogenic effect of APP-Swedish mutation in familial Alzheimer's disease.
Science translational medicine
2022; 14 (667): eabn9380
Mutations in beta-amyloid (Abeta) precursor protein (APP) cause familial Alzheimer's disease (AD) probably by enhancing Abeta peptides production from APP. An antibody targeting Abeta (aducanumab) was approved as an AD treatment; however, some Abeta 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 Abeta 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 Abeta, 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 Abeta. These data are consistent with the relative inefficacy of BACE1 and anti-Abeta treatments in AD and the chronic nature of AD pathogenesis, suggesting that AD pathogenesis is not simply caused by overproduction of toxic Abeta but rather by a long-term effect of elevated Abeta concentrations.
View details for DOI 10.1126/scitranslmed.abn9380
View details for PubMedID 36260691