Fig. 3. Brain Aβ seeding activity after short-term and chronic BACE1 inhibition.

a Brain extracts from all mice within a group were pooled, serially diluted, and intracerebrally (IC) injected into the hippocampus of young, pre-depositing 2- to 3-mo old female APP23 host mice (n = 4–6 per extract; for exact numbers see Supplementary Fig. 1b). APP23 host mice were analyzed for Aβ deposition using immunohistochemistry (CN6 and Congo Red) 6 months later. Illustrations were partly created with BioRender.com. b Treatment groups for which SD₅₀ was determined (short-term for young, adult, aged; young-chronic). c SD₅₀ (defined as the log 10 of the brain extract dilution at which 50% of the host mice showed induced Aβ deposition) was computed for each treatment group and complemented with the trajectories of SD₅₀ from a former study (see Supplementary Fig. 1b, c and Methods). BI treatments in amyloid-laden adult and aged mice did not consistently affect the seeding activity. When BI treatment was initiated before appreciable Aβ deposition was present (i.e., at 1.5 mo of age) SD₅₀ almost reached control levels after the 3-month treatment. After chronic treatment, SD₅₀ was about 1 log (10-fold dilution) below the control (i.e., below the saturated seeding activity). Since the chronic treatment is, in a sense, an extension of the 3-month treatment, the line is drawn from the 3-month treatments to the end of the chronic treatment, suggesting that the SD₅₀ remains at this level when Aβ generation is continuously blocked.