Alberto Siddu

All Publications

• Aggregation shifts amyloid-β peptides from synaptogenic to synaptotoxic. The Journal of clinical investigation Siddu, A., Natale, S., Wong, C. H., Shaye, H., Südhof, T. C. 2025

  Abstract

  Whether amyloid-β (Aβ) peptides are synaptogenic or synaptotoxic remains a pivotal open question in Alzheimer's disease research. Here, we chronically treated human neurons with precisely controlled concentrations of chemically defined synthetic Aβ40, Aβ42, and Aβ42arctic peptides that exhibit distinct aggregation propensities. Remarkably, chronic exposure of human neurons to free Aβ40 at higher concentrations or to free Aβ42 at lower concentrations potently promoted synapse formation. In contrast, aggregated Aβ42 or Aβ42arctic at higher concentrations were neurotoxic and synaptotoxic. The synaptotoxic effects of Aβ peptides manifested as an initial contraction of the synaptic vesicle cluster followed by synapse loss. Aβ40 and Aβ42 peptides with scrambled or inverted sequences were inactive. Thus, our experiments reveal that Aβ peptides exhibit an aggregation-dependent functional dichotomy that renders them either synaptogenic or synaptotoxic, thereby providing insight into how Aβ peptides straddle a thin line between physiological synapse organization and pathological synapse disruption. Among others, our data suggest that Alzheimer's disease therapies might aim to shift the balance of Aβ peptides from the aggregated to the free state instead of suppressing all Aβ peptides.

  View details for DOI 10.1172/JCI193407

  View details for PubMedID 41026542

• Synaptogenic effect of APP-Swedish mutation in familial Alzheimer's disease. Science translational medicine Zhou, B., Lu, J. G., Siddu, A., Wernig, M., Sudhof, T. C. 2022; 14 (667): eabn9380

  Abstract

  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