Supplementary Materials

The PDF file includes:

• Materials and Methods
• Fig. S1. Representative kymographs for BACE1-mCherry and GFP-GGA3 cotransport experiments in Fig. 2D.
• Fig. S2. Representative images for PI analysis in Fig. 3B.
• Fig. S3. Colocalization analysis for BACE1-mCherry with EEA1 and LAMP2.
• Fig. S4. Representative image for BACE1-mCherry and LAMP2 in Gga3^−/− axonal swelling.
• Fig. S5. NFH staining of hippocampal CA1 axonal bundles and BACE1 accumulation in the cerebellum and hippocampus of Gga3^−/− mice.
• Fig. S6. Images for BACE1-mcherry and GFP-GGA3 channels corresponding to axon in Fig. 6A.
• Fig. S7. Supplementary data and analysis related to BACE inhibition experiments.
• Fig. S8. Representative images of cerebella and hippocampi from MBi-3–treated mice.
• Fig. S9. Images for BACE1-mcherry and GFP-GGA3 channels corresponding to axons in Fig. 7C.
• Table S1. [MBi-3] micromolars—Pharmacokinetics (PK) analysis summary.
• Table S2. Genetics dataset description.
• Table S3. Selected single variants, showing nominal association with AD in one of the datasets.
• Table S4. Summary of the antibodies used throughout this study.
• Legend for data file S1
• References (60–64)

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Other Supplementary Material for this manuscript includes the following:

• Movie S1 (.mp4 format). BACE1-mCherry and GFP-GGA3 axonal trafficking in wild-type neurons.
• Movie S2 (.mp4 format). BACE1-mCherry and synaptophysin-GFP axonal trafficking in Gga3^+/+ and Gga3^−/− neurons.
• Movie S3 (.mov format). Three-dimensional reconstruction of BACE1-mCherry and LAMP2 in Gga3^−/− axonal swelling.
• Movie S4 (.mp4 format). BACE1-mCherry and synaptophysin-GFP accumulation in axonal swellings in Gga3^−/− neurons.
• Movie S5 (.mp4 format). Representative movies for BACE1-mCherry trafficking experiments in Fig. 6.
• Movie S6 (.mp4 format). Representative movies for BACE1-mCherry trafficking experiments in Fig. 7.
• Data file S1. Individual-level data file n < 20 (provided as separate Excel file).