Dataset Information

Amyloid-precursor Like Proteins APLP1 and APLP2 Are Dispensable for Normal Development of the Neonatal Respiratory Network.

ABSTRACT: Recent studies using animal models indicated that the members of the amyloid precursor protein (APP) gene family are important for the formation, maintenance, and plasticity of synapses. Despite this, the specific role of the APP homologs APLP1 and APLP2 within the CNS and PNS is still poorly understood. In contrast to the subtle phenotypes of single mutants, double knockout mice (DKO) lacking APP/APLP2 or APLP1/APLP2 die within the first day after birth. Whereas APP/APLP2-DKO mice show severe deficits of neuromuscular morphology and transmission, the underlying cause of lethality of APLP1/APLP2-DKO mice remains unclear. Since expression of both proteins was confirmed by in situ hybridization, we aimed to test the role of APLP1/APLP2 in the formation and maintenance of synapses in the brainstem, and assessed a potential dysfunction of the most vital central neuronal network in APLP1/APLP2-DKO mice by analyzing the respiratory network of the medulla. We performed in vivo unrestrained whole body plethysmography in newborn APLP1/APLP2-DKO mice at postnatal day zero. Additionally, we directly tested the activity of the respiratory network in an acute slice preparation that includes the pre-Bötzinger complex. In both sets of experiments, no significant differences were detected regarding respiratory rate and cycle variability, strongly arguing against central respiratory problems as the primary cause of death of APLP1/APLP2-DKO mice. Thus, we conclude that APLP1 and APLP2 are dispensable for the development of the network and the generation of a normal breathing rhythm.

SUBMITTER: Han K

PROVIDER: S-EPMC5479907 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Amyloid-precursor Like Proteins APLP1 and APLP2 Are Dispensable for Normal Development of the Neonatal Respiratory Network.

Han Kang K Müller Ulrike C UC Hülsmann Swen S

Frontiers in molecular neuroscience 20170622

Recent studies using animal models indicated that the members of the amyloid precursor protein (APP) gene family are important for the formation, maintenance, and plasticity of synapses. Despite this, the specific role of the APP homologs APLP1 and APLP2 within the CNS and PNS is still poorly understood. In contrast to the subtle phenotypes of single mutants, double knockout mice (DKO) lacking APP/APLP2 or APLP1/APLP2 die within the first day after birth. Whereas APP/APLP2-DKO mice show severe d ...[more]

PMID: 28690498

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Project description:Proteolytic processing of the Amyloid Precursor Protein (APP) produces beta-amyloid (A?) peptide fragments that accumulate in Alzheimer's Disease (AD), but APP may also regulate multiple aspects of neuronal development, albeit via mechanisms that are not well understood. APP is a member of a family of transmembrane glycoproteins expressed by all higher organisms, including two mammalian orthologs (APLP1 and APLP2) that have complicated investigations into the specific activities of APP. By comparison, insects express only a single APP-related protein (APP-Like, or APPL) that contains the same protein interaction domains identified in APP. However, unlike its mammalian orthologs, APPL is only expressed by neurons, greatly simplifying an analysis of its functions in vivo. Like APP, APPL is processed by secretases to generate a similar array of extracellular and intracellular cleavage fragments, as well as an A?-like fragment that can induce neurotoxic responses in the brain. Exploiting the complementary advantages of two insect models (Drosophila melanogaster and Manduca sexta), we have investigated the regulation of APPL trafficking and processing with respect to different aspects of neuronal development. By comparing the behavior of endogenously expressed APPL with fluorescently tagged versions of APPL and APP, we have shown that some full-length protein is consistently trafficked into the most motile regions of developing neurons both in vitro and in vivo. Concurrently, much of the holoprotein is rapidly processed into N- and C-terminal fragments that undergo bi-directional transport within distinct vesicle populations. Unexpectedly, we also discovered that APPL can be transiently sequestered into an amphisome-like compartment in developing neurons, while manipulations targeting APPL cleavage altered their motile behavior in cultured embryos. These data suggest that multiple mechanisms restrict the bioavailability of the holoprotein to regulate APPL-dependent responses within the nervous system. Lastly, targeted expression of our double-tagged constructs (combined with time-lapse imaging) revealed that APP family proteins are subject to complex patterns of trafficking and processing that vary dramatically between different neuronal subtypes. In combination, our results provide a new perspective on how the regulation of APP family proteins can be modulated to accommodate a variety of cell type-specific responses within the embryonic and adult nervous system.

Dataset Information

Amyloid-precursor Like Proteins APLP1 and APLP2 Are Dispensable for Normal Development of the Neonatal Respiratory Network.

Publications

Amyloid-precursor Like Proteins APLP1 and APLP2 Are Dispensable for Normal Development of the Neonatal Respiratory Network.

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