Neuropathology of Mice Carrying Mutant APPswe and/or PS1M146L Transgenes: Alterations in the p75 Cholinergic Basal Forebrain Septohippocampal Pathway

Cholinergic basal forebrain (CBF) projection systems are defective in late Alzheimer's disease (AD). We examined the brains of 12-month-old singly and doubly transgenic mice overexpressing mutant amyloid precursor protein (APP_swe) and/or presenilin-1 (PS1_M146L) to investigate the effects of these AD-related genes on plaque and tangle pathology, astrocytic expression, and the CBF projection system. Two types of β-amyloid (Aβ)-immunoreactive (ir) plaques were observed: type 1 were darkly stained oval and elongated deposits of Aβ, and type 2 were diffuse plaques containing amyloid fibrils. APP_swe and PS1_M146L mouse brains contained some type 1 plaques, while the doubly transgenic (APP_swe/PS1_M146L) mice displayed a greater abundance of types 1 and 2 plaques. Sections immunostained for the p75 NGF receptor (p75^NTR) revealed circular patches scattered throughout the cortex and hippocampus of the APP_swe/PS1_M146L mice that contained Aβ, were innervated by p75^NTR-ir neurites, but displayed virtually no immunopositive neurons. Tau pathology was not seen in any transgenic genotype, although a massive glial response occurred in the APP_swe/PS1_M146L mice associated with amyloid plaques. Stereology revealed a significant increase in p75^NTR-ir medial septal neurons in the APP_swe and PS1_M146L singly transgenic mice compared to the APP_swe/PS1_M146L mice. No differences in size or optical density of p75^NTR-ir neurons were observed in these three mutants. p75^NTR-ir fibers in hippocampus and cortex were more pronounced in the APP_swe and PS1_M146L mice, while the APP_swe/PS1_M146L mice showed the least p75^NTR-ir fiber staining. These findings suggest a neurotrophic role for mutant APP and PS1 upon cholinergic hippocampal projection neurons at 12 months of age.