Presenilin 1 transgene addition to amyloid precursor protein overexpressing transgenic rats increases amyloid beta 42 levels and results in loss of memory retention.

Cansu Agca,Todd R Schachtman,Diana Klakotskaia,Yuksel Agca,Anthony W Chan,James J Lah

doi:10.1186/s12868-016-0281-8

Cansu Agca, Todd R Schachtman + Show 4 more

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https://doi.org/10.1186/s12868-016-0281-8

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Journal: BMC neuroscience	Publication Date: Jul 7, 2016
Citations: 32	License type: cc-by

Affiliation: University of Missouri, Emory University

Abstract

BackgroundWe previously reported the production of transgenic rats (APP21 line) that over-express human amyloid precursor protein (APP) containing Swedish and Indiana mutations. In order to generate a better model for Alzheimer’s disease (AD), the APP21 rat line was used to generate double transgenic line that over-expressed Presenilin 1 (PS1) with L166P mutation in addition to APP transgene (APP + PS1 line).ResultsThirty-two double transgenic founders were generated and the ultimate transgenic founder was selected based on PS1 transgene copy number and level of amyloid-beta (Aβ)42 peptide. The APP + PS1 double transgenic rats had 38 times more PS1 in brains compared to APP rats. Behavioral assessment using Barnes maze showed that APP + PS1 rats exhibited a larger learning and memory deficit than APP21 rats. Double transgenic rats also produced more Aβ42. Histological examination of the brains showed that the APP21 rat line displayed neurofibrillary tangles and in contrast, the APP + PS1 line showed chromatolysis in hippocampal neurons and neuronal loss in CA3 region of hippocampus.ConclusionsDue to the separate segregation of APP and PS1 transgenes in APP + PS1 double transgenic rats, this transgenic line may be a valuable model for studying the effects of various levels of APP and PS1 transgenes on various aspects of brain pathologies associated with the AD phenotype.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-016-0281-8) contains supplementary material, which is available to authorized users.

Highlights

We previously reported the production of transgenic rats (APP21 line) that over-express human amyloid precursor protein (APP) containing Swedish and Indiana mutations
The human Presenilin 1 (PS1) cDNA coding region corresponding to 2851688 bases of PS1 variant 1 (GenBank Accession number NM_000021.3) with L166P mutation was cloned into the Lentivial vector containing ubiquitin-C (Ubi-C) and enhanced green fluorescence protein cassette [17] in place of the eGFP coding sequence
APP21‐PS1 double transgenic founders Forty-five rats were born from the lentiviral vector which contained PS1 transgene-injected embryos and 32 of them were PCR positive for the PS1 transgene

Summary

Introduction

We previously reported the production of transgenic rats (APP21 line) that over-express human amyloid precursor protein (APP) containing Swedish and Indiana mutations. Alzheimer’s disease is associated with the over-production and reduced clearance of amyloid-beta (Aβ) peptides [19]. Cleavage of amyloid-β precursor protein (APP) by the presenilin (PS) 1 enzyme results in the release of Aβ peptides, which aggregate and form Aβ plaques in the brain. These Aβ plaques and neurofibrillary tangles are the two primary pathological manifestations of AD in the brain. The reduction of PS1 mRNA using siRNA against PS1 reduced Aβ42 in cultured cells [11] which suggests that lower levels of PS1 lead to decreased production of Aβ42

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