Abstract
BackgroundAlzheimer's disease (AD) is a devastating neurodegenerative disorder that affects a large and growing number of elderly individuals. In addition to idiopathic disease, AD is also associated with autosomal dominant inheritance, which causes a familial form of AD (FAD). Some instances of FAD have been linked to mutations in the β-amyloid protein precursor (APP). Although there are numerous mouse AD models available, few rat AD models, which have several advantages over mice, have been generated.ResultsFischer 344 rats expressing human APP driven by the ubiquitin-C promoter were generated via lentiviral vector infection of Fischer 344 zygotes. We generated two separate APP-transgenic rat lines, APP21 and APP31. Serum levels of human amyloid-beta (Aβ)40 were 298 pg/ml for hemizygous and 486 pg/ml for homozygous APP21 animals. Serum Aβ42 levels in APP21 homozygous rats were 135 pg/ml. Immunohistochemistry in brain showed that the human APP transgene was expressed in neurons, but not in glial cells. These findings were consistent with independent examination of enhanced green fluorescent protein (eGFP) in the brains of eGFP-transgenic rats. APP21 and APP31 rats expressed 7.5- and 3-times more APP mRNA, respectively, than did wild-type rats. Northern blots showed that the human APP transgene, driven by the ubiquitin-C promoter, is expressed significantly more in brain, kidney and lung compared to heart and liver. A similar expression pattern was also seen for the endogenous rat APP. The unexpected similarity in the tissue-specific expression patterns of endogenous rat APP and transgenic human APP mRNAs suggests regulatory elements within the cDNA sequence of APP.ConclusionThis manuscript describes the generation of APP-transgenic inbred Fischer 344 rats. These are the first human AD model rat lines generated by lentiviral infection. The APP21 rat line expresses high levels of human APP and could be a useful model for AD. Tissue-specific expression in the two transgenic rat lines and in wild-type rats contradicts our current understanding of APP gene regulation. Determination of the elements that are responsible for tissue-specific expression of APP may enable new treatment options for AD.
Highlights
Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects a large and growing number of elderly individuals
AD can be inherited in an autosomal dominant manner, which causes a familial form of AD (FAD) that usually emerges at younger ages than does idiopathic AD [2]
Promoter Characterization and Selection Comparison of enhanced green fluorescent protein expression driven from ubiquitin-C (Ubi-C), cytomegalovirus (CMV), or platelet-derived growth factor (PDGF) promoters in SD rat brains after stereotaxic injection of lentivirus showed that the Ubi-C promoter yielded consistently superior eGFP expression than did the CMVeGFP and PDGF-eGFP viruses
Summary
Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects a large and growing number of elderly individuals. FAD has been linked to mutations in the β-amyloid precursor protein (APP) [3], as well as presenilin 1 [4] and presenilin 2 [5], which are critical components of the γsecretase complex that liberates the amyloid-β peptide (Aβ) from membranes. Two predominant forms of Aβ, Aβ40 and Aβ42, result from the proteolytic cleavage of APP by β- and γsecretases [6]. Because it is highly amyloidogenic, Aβ42 is believed to play a important role in the pathogenesis of AD [7]
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