Murine Aβ over-production produces diffuse and compact Alzheimer-type amyloid deposits.

Guilian Xu,Anthony T. Yachnis,Chunhua Fu,Susan E. Fromholt,Yong Ran,Todd E. Golde,David R. Borchelt

doi:10.1186/s40478-015-0252-9

Abstract

IntroductionTransgenic overexpression of amyloid precursor protein (APP) genes that are either entirely human in sequence or have humanized Aβ sequences can produce Alzheimer-type amyloidosis in mice, provided the transgenes also encode mutations linked to familial Alzheimer’s Disease (FAD). Although transgenic mice have been produced that overexpress wild-type mouse APP, no mice have been generated that express mouse APP with FAD mutations. Here we describe two different versions of such mice that produce amyloid deposits consisting of entirely of mouse Aβ peptides. One line of mice co-expresses mouse APP-Swedish (moAPPswe) with a human presenilin exon-9 deleted variant (PS1dE9) and another line expresses mouse APP-Swedish/Indiana (APPsi) using tetracycline-regulated vectors (tet.moAPPsi). ResultsBoth lines of mice that produce mouse Aβ develop amyloid deposits, with the moAPPswe/PS1dE9 micedeveloping extracellular compact, cored, neuritic deposits that primarily localize to white matter tracts andmeningial layers, whereas the tet.moAPPsi mice developed extracellular diffuse cortical/hippocampal deposits distributed throughout the parenchyma.ConclusionsThese findings demonstrate that murine Aβ peptides have the capacity to produce amyloid deposits that are morphologically similar to deposits found in human AD provided the murine APP gene harbors mutations linked to human FAD.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0252-9) contains supplementary material, which is available to authorized users.

Highlights

Transgenic overexpression of amyloid precursor protein (APP) genes that are either entirely human in sequence or have humanized Aβ sequences can produce Alzheimer-type amyloidosis in mice, provided the transgenes encode mutations linked to familial Alzheimer’s Disease (FAD)
Both lines of mice that produce mouse Aβ develop amyloid deposits, with the moAPPswe/PS1 harboring the FAD exon-9 deletion (PS1dE9) micedeveloping extracellular compact, cored, neuritic deposits that primarily localize to white matter tracts andmeningial layers, whereas the tet.moAPPsi mice developed extracellular diffuse cortical/hippocampal deposits distributed throughout the parenchyma
These findings demonstrate that murine Aβ peptides have the capacity to produce amyloid deposits that are morphologically similar to deposits found in human AD provided the murine APP gene harbors mutations linked to human FAD

Summary

Introduction

Transgenic overexpression of amyloid precursor protein (APP) genes that are either entirely human in sequence or have humanized Aβ sequences can produce Alzheimer-type amyloidosis in mice, provided the transgenes encode mutations linked to familial Alzheimer’s Disease (FAD). Transgenic mice have been produced that overexpress wild-type mouse APP, no mice have been generated that express mouse APP with FAD mutations. We describe two different versions of such mice that produce amyloid deposits consisting of entirely of mouse Aβ peptides. Mutations in the amino acid sequence of the amyloid precursor protein (APP) influence its cleavage by three types of endo-proteases termed α, β, and γ-secretase [8, 16]. For wild-type APP sequence, BACE 1 generally cleaves APP at the +11 site, and after cleavage by γ-secretase, Aβ peptides 11–40 and 11–42 are produced [6]. Amyloid deposits similar to human AD have been described in many species of aged animals including non-human

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