Abstract
It is widely accepted that amyloid precursor protein (APP) plays a central role in the pathogenesis of Alzheimer's disease. In addition, APP has been proposed to have functions in numerous biological processes including neuronal proliferation, differentiation, migration, axon guidance, and neurite outgrowth, as well as in synapse formation and function. However, germline knockout of APP yields relatively subtle phenotypes, and brain development appears grossly normal. This is thought to be due in part to functional compensation by APP family members and other type I transmembrane proteins. Here, we have generated a conditional mouse knockout for APP that is controlled temporally using CreER and tamoxifen administration. We show that total cortical expression of APP is reduced following tamoxifen administration during embryonic time points critical for cortical lamination, and that this results in displacement of Reelin-positive cells below the cortical plate with a concurrent elevation in Reelin protein levels. These results support a role for APP in cortical lamination and demonstrate the utility of a conditional knockout approach in which APP can be deleted with temporal control in vivo. This new tool should be useful for many different applications in the study of APP function across the mammalian life span.
Highlights
Amyloid precursor protein (APP) is a highly studied protein, primarily due to its role in Alzheimer’s disease (AD)
In order to address the discrepancy between shRNA-induced APP reduction and germline APP knockout and to clarify the role of APP in cortical cell placement in mammalian cells, we have developed a tool for regulated temporal disruption of genomic APP in mice
In order to confirm that deletion of exon 3 was sufficient to eliminate APP expression, APPflox mice were crossed with transgenic mice expressing Cre under transcriptional control of the human cytomegalovirus minimal promoter (CMV-Cre)
Summary
Amyloid precursor protein (APP) is a highly studied protein, primarily due to its role in Alzheimer’s disease (AD). Dozens of missense mutations have been identified in APP that result in the alteration of the type and amount of amyloid beta (Aβ) generated (reviewed in [1]). These mutations result in an early-onset form of AD, and they are fully penetrant and dominantly inherited. Aβ is the primary component of amyloid plaques, the pathological hallmark of earlyand late-onset AD. As Alzheimer’s disease candidate drugs seek to chronically target APP processing, understanding the functions of APP in the healthy brain is essential
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