title: Neuropathology of mice carrying mutant APP(swe) and/or PS1(M146L) transgenes: alterations in the p75(NTR) cholinergic basal forebrain septohippocampal pathway.
abstract: 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 beta-amyloid (Abeta)-immunoreactive (ir) plaques were observed: type 1 were darkly stained oval and elongated deposits of Abeta, 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 Abeta, 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.
authors.affiliation: Department of Neurological Sciences, Rush Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA.
authors.forename: S
authors.initials: S
authors.lastname: Jaffar
authors.forename: S E
authors.initials: SE
authors.lastname: Counts
authors.forename: S Y
authors.initials: SY
authors.lastname: Ma
authors.forename: E
authors.initials: E
authors.lastname: Dadko
authors.forename: M N
authors.initials: MN
authors.lastname: Gordon
authors.forename: D
authors.initials: D
authors.lastname: Morgan
authors.forename: E J
authors.initials: EJ
authors.lastname: Mufson
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000032:analysis; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000473:pathology*; D002540:Cerebral Cortex / Q000473:pathology; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009412:Nerve Fibers / Q000473:pathology; D016501:Neurites / Q000473:pathology; D009474:Neurons / Q000473:pathology; D058225:Plaque, Amyloid / Q000473:pathology; D053764:Presenilin-1; D016548:Prosencephalon / Q000473:pathology; D020800:Receptor, Nerve Growth Factor / Q000032:analysis
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D020800:Receptor, Nerve Growth Factor