Human IgG immunoreactivity is detected in the brain after peripheral administration of IVIG. To study whether IVIG could penetrate the BBB to reach brain parenchyma, APP/PS1 mice were injected i.p. with IVIG 1 g/kg or saline starting at the age of 4 months. The IVIG was identified from cryostat-cut mouse brain sections with anti-human IgG. IVIG penetrated BBB as evidenced with intensive human IgG staining in the mouse hippocampus (A) with a clear anterior-posterior gradient with the highest immunoreactivity at the septal end of the hippocampus adjacent to the choroid plexus. Also, strong immunoreactivity was observed lining the ventricles (A). The intensity of human IgG immunoreactivity was increased with the duration of IVIG treatment from 1 to 14 weeks of IVIG admininistration (C). Saline-treated mice were devoid of specific immunoreactivity for anti-human IgG (B). In the hippocampus, Aβ deposits appeared as stippled patterns of aggregated material covered with immunoreactivity for human IgG (black arrows) (D). After a single intrahippocampal injection of IVIG the IgG immunoreactivity was spread homogeneously throughout the hippocampus (E) while stronger IgG immunoreactivity was observed as stippled patterns (E). Scale bars 200 μm (A, B, E) and 50 μm (D).