Intraneuronal Aβ immunoreactivity decreases as plaque number increases. A–G: Using Scion image software (from NIH), we measured intraneuronal Aβ immunoreactivity and extracellular Aβ load in the hippocampus of 12-to 18-month-old 3xTg-AD homozygous mice (n = 6 per group, three sections per mouse, three pictures per sections). Representative low- and high-magnification microphotographs of the hippocampus of 12-month-old (A, B) and 18-month-old (C, D) 3xTg-AD mice immunostained with an anti-Aβ42-specific antibody. E: Quantitative analysis of intraneuronal Aβ immunoreactivity shows a significant decrease in levels between 12 and 18 months of age (P < 0.05). F: In contrast, plaque numbers significantly increase during this time (P < 0.01). G: A significant inverse relationship exists between intraneuronal Aβ immunoreactivity and number of amyloid plaques in mice of different ages (n = 20).