Hippocampal CA3 brain region selectively vulnerable in APP, α-syn, and α-syn/APP tg mice. Immunocytochemical analysis was performed in the hippocampal CA3 pyramidal layer. A. Representative confocal, MAP 2- (dendritic marker) and synaptophysin- (pre-synaptic terminal marker), and photomicrographs of GFAP- (astroglial cells) and Iba-1- (microglial cells) ir. MAP 2-ir found in neuronal cell bodies and dendrites, was reduced in APP, α-syn and α-syn/APP tg mice. Synaptophysin was abundant in punctate staining in non-tg pre-synaptic nerve terminals and reduced in α-syn and α-syn/APP tg mice. GFAP-positive astroglial cells had small cell bodies with short processes in the non-tg mice, while APP, α-syn, and α-syn/APP tg mice had GFAP-positive astroglia with enlarged cell bodies and extended processes. Non-tg mice displayed strongly immunoreactive discrete Iba-1-immunoreactive microglia, which increased in APP, α-syn and α-syn/APP tg mice B. The percent area of MAP 2-ir neuropil was significantly decreased in all tg lines compared to non-tg mice, with the greatest loss in the α-syn/APP double tg mice. C. The percent of synaptophysin-ir neuropil area revealed a significant reduction in α-syn tg mice and further reduction in α-syn/APP tg mice. D. Optical density image analysis revealed a significant increase in GFAP-ir in the APP and α-syn tg mice, which was greatest in α-syn/APP double tg mice compared to non-tg mice. E. Image analysis confirmed a significant increase in the number of Iba-1-positive cells in APP and α-syn single tg mice, which was greatest in α-syn/APP double tg mice. * = p-value < 0.05 and ** = p-value < 0.01 by one-way ANOVA and Dunnett’s post hoc analysis compared to non-tg mice. # = p-value < 0.05 by one-way ANOVA and Tukey-Kramer post hoc analysis when compared to α-syn/APP tg mice. For each analysis, N = 6 (3–4 months old) mice from each line were utilized.