Fig. 3. Human APOE variants differentially modulate amyloidosis progression.

(A) Representative in vivo two-photon images of amyloid deposition in APP/PS1 mice 1 week (T0), 1 month (T1), and 2 months (T2) after injection of AAV4 carrying GFP, APOE2, APOE3, or APOE4. An intravenous injection of Texas red dextran (70,000 daltons) was performed before imaging so that the same fields of view could be followed over time. Few new amyloid plaques (in green, detected after intraperitoneal injection of the amyloid fluorescent probe methoxy-XO₄) could be detected (blue arrows), whereas occasional deposits initially visible were not detected after 1 or 2 months (yellow arrows). Scale bar, 100 μm. (B) Evaluation of the volumetric cortical density of amyloid deposits over a 2-month period after intraventricular injection of AAV4-GFP, AAV4-APOE2, AAV4-APOE3, or AAV4-APOE4. Six to eight fields of view were longitudinally imaged for each animal. The density of plaques was calculated per volume of cortex and was normalized to the initial value for each animal at baseline (T0). (C) Linear regression fit of amyloidosis progression over 2 months after gene transfer shows that only AAV4-APOE4 induced a significant positive slope during this period. n = 4 AAV4-GFP, n = 4 AAV4-APOE2, n = 6 AAV4-APOE3, and n = 5 AAV4-APOE4 mice. *P < 0.05 using mixed-effects model, with a random effect for mouse and fixed effects for vector, time, and baseline volumetric density.