Clearance of beta-amyloid and tau aggregates is size dependent and altered by an inflammatory challenge.
Creators: name: Fertan, Emre
name: Hung, Christy
name: Danial, John SH
name: Lam, Jeff YL
name: Preman, Pranav
name: Albertini, Giulia
name: English, Elizabeth A
name: Böken, Dorothea
name: Livesey, Frederick J
name: De Strooper, Bart
name: Patani, Rickie
name: Klenerman, David
Publisher: name: The Francis Crick Institute
Year: 2025
Subjects: classificationCode: Stem Cells
subject: Stem Cells
classificationCode: Computational & Systems Biology
subject: Computational &amp; Systems Biology
classificationCode: Neurosciences
subject: Neurosciences
subject: FOS: Clinical medicine
classificationCode: Human Biology & Physiology
subject: Human Biology &amp; Physiology
classificationCode: Model organisms
subject: Model organisms
classificationCode: Biochemistry & Proteomics
subject: Biochemistry &amp; Proteomics
classificationCode: Cell Biology
subject: Cell Biology

description: Extracellular beta-amyloid aggregation and inflammation are in a complex and not fully understood interplay during hyperphosphorylated tau aggregation and pathogenesis of Alzheimer's disease. Our group has previously shown that an immune challenge with tumour necrosis factor alpha can alter extracellular beta-sheet containing aggregates in human-induced pluripotent stem cell-derived cortical neurons carrying familial Alzheimer's disease-related presenilin 1 mutations. Here, using single-molecule detection and super-resolution imaging techniques, we quantified and characterized the intra- and extracellular beta-amyloid and AT8-positive tau aggregates. Our results indicate a pre-existing Alzheimer's disease-like pathology caused by the presenilin 1 mutation, with increased beta-amyloid aggregates in both the cell lysate and conditioned media compared to isogenic controls and also increased intracellular tau aggregates. The main effect of tumour necrosis factor alpha treatment on presenilin 1 neurons was the formation of larger intracellular beta-amyloid aggregates. In contrast, isogenic controls showed more significant changes with tumour necrosis factor alpha treatment with an increase in beta-amyloid aggregates in the media but not intracellularly and an increase in tau aggregates in both the media and cell lysate, suggesting a chronic inflammation-driven mechanism for the development of sporadic Alzheimer's disease. Remarkably, we also found significant morphological differences between intra- and extracellular beta-amyloid and tau aggregates in human-induced pluripotent stem cell-derived cortical neurons, suggesting these neurons can only clear aggregates when small, and that larger aggregates stay inside the neurons. While majority of the beta-amyloid aggregates were cleared into the media, a greater portion of the tau aggregates remained intracellular. This size-dependent aggregate clearance was also shown to be conserved in vivo, using soaked and homogenized mouse and human post-mortem Alzheimer's disease brain samples. As such, our results are proposing a previously unknown, size-dependent aggregate clearance mechanism, which can possibly explain the intracellular aggregation of tau and extracellular aggregation of beta-amyloid.