Neuropathology of mice carrying mutant APPswe and/or PS1M146L transgenes: Alterations in the p75NTR cholinergic basal forebrain septohippocampal pathway

Document Type

Article

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 (APPswe) and/or presenilin-1 (PS1M146L) 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. APPswe and PS1M146L mouse brains contained some type 1 plaques, while the doubly transgenic (APPswe/PS1M146L) mice displayed a greater abundance of types 1 and 2 plaques. Sections immunostained for the p75 NGF receptor (p75NTR) revealed circular patches scattered throughout the cortex and hippocampus of the APPswe/PS1M146L mice that contained Aβ, were innervated by p75NTR-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 APPswe/PS1M146L mice associated with amyloid plaques. Stereology revealed a significant increase in p75NTR-ir medial septal neurons in the APPswe and PS1M146L singly transgenic mice compared to the APPswe/PS1M146L mice. No differences in size or optical density of p75NTR-ir neurons were observed in these three mutants. p75NTR-ir fibers in hippocampus and cortex were more pronounced in the APPswe and PS1M146L mice, while the APPswePS1M146L mice showed the least p75NTR-ir fiber staining. These findings suggest a neurotrophic role for mutant APP and PS1 upon cholinergic hippocampal projection neurons at 12 months of age. © 2001 Academic Press.

Keywords

Alzheimer's, Amyloid, Basal forebrain, Cholinergic, Mice, Neuropathology, Neurotrophin, Presenilin, Stereology, Transgenic

Publication Date

1-1-2001

Publication Title

Experimental Neurology

ISSN

00144886

Volume

170

Issue

2

First Page

227

Last Page

243

Digital Object Identifier (DOI)

10.1006/exnr.2001.7710

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