Amyloid Precursor Proteins Interact with the Heterotrimeric G Protein Go in the Control of Neuronal Migration

Ramaker, Jenna M.; Swanson, Tracy L.; Copenhaver, Philip F.

doi:10.1523/jneurosci.1146-13.2013

Cited by 38 publications

(58 citation statements)

References 99 publications

(88 reference statements)

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“…In particular, a targeted mutation in the YENPTY motif located in the intracellular domain of APP and involved in the interaction of APP with other proteins such as FE65 and DAB1 ( Figure 2) abrogates the rescue effect of full-length APP in line with the observation that DAB1 and FE65 (Sabo et al, 2001) are also required for migration. Other intracellular proteins such as disrupted-in-schizophrenia 1 (DISC1) (Young-Pearse et al, 2010) and the heterotrimeric G protein Go (Ramaker et al, 2013) may also interact with APP to regulate neuronal migration. In this regard, migration ordinarily depends on linking interactions with the extracellular matrix to the cytoskeleton and motor proteins.…”

Section: Reviewmentioning

confidence: 99%

Cellular Functions of the Amyloid Precursor Protein from Development to Dementia

2015

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Amyloid precursor protein (APP) is a key player in Alzheimer's disease (AD). The Aβ fragments of APP are the major constituent of AD-associated amyloid plaques, and mutations or duplications of the gene coding for APP can cause familial AD. Here we review the roles of APP in neuronal development, signaling, intracellular transport, and other aspects of neuronal homeostasis. We suggest that APP acts as a signaling nexus that transduces information about a range of extracellular conditions, including neuronal damage, to induction of intracellular signaling events. Subtle disruptions of APP signaling functions may be major contributors to AD-causing neuronal dysfunction.

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Section: Reviewmentioning

confidence: 99%

Cellular Functions of the Amyloid Precursor Protein from Development to Dementia

2015

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“…Numerous studies have demonstrated that APP can function as a neuronal receptor, capable of binding a variety of candidate ligands and transducing intracellular responses that modulate cell adhesion, neuronal outgrowth, and migration (Osterfield et al, 2008; Nikolaev et al, 2009; Rama et al, 2012; Rice et al, 2013). In support of this model, APP can be detected in the growing processes and focal adhesion complexes of cultured cells, suggesting that APP signaling might regulate the cytoskeletal dynamics required for neuronal outgrowth and migration (Sabo et al, 2003; Wang et al, 2005; Young-Pearse et al, 2007; Ramaker et al, 2013). In particular, members of the APP family can function as unconventional G protein-coupled receptors (Nishimoto et al, 1993; Giambarella et al, 1997; Swanson et al, 2005), transducing responses to local cues via the heterotrimeric G protein Goα to regulate neuronal guidance (Brouillet et al, 1999; Ramaker et al, 2013, 2016).…”

Section: Introductionmentioning

confidence: 91%

Amyloid Precursor Proteins Are Dynamically Trafficked and Processed during Neuronal Development

Ramaker

Cargill

Swanson

et al. 2016

Front. Mol. Neurosci.

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Proteolytic processing of the Amyloid Precursor Protein (APP) produces beta-amyloid (Aβ) 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 Aβ-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.

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“…APP is created in the endoplasmic reticulum, and is transported between the cell membrane and the Golgi apparatus (Zheng et al 2012). Within the neuron, increases in synaptic transmission and oxidative stress promote an increase in endocytosis of APP from the cell membrane into endolysosomes (Matsuda et al 2003; Ramaker et al 2013; Zheng et al 2012). Within the endolysosomes, APP is cleaved by secretases [including alpha (α), beta (β) (aka BACE-1), and gamma (γ)] to create amyloid-beta monomers of various lengths (between 39–43 amino acids) including the 42 amino acid length protein Aβ42 and soluble APP (sAPP) peptide fragments (LaFerla et al 2007).…”

Section: Multiple Amyloid Synthesis and Degradation Pathways Exist Inmentioning

confidence: 99%

Role of HIV in Amyloid Metabolism

Ortega

Ances

2014

J Neuroimmune Pharmacol

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HIV infection has changed from an acute devastating disease to a more chronic illness due to combination anti-retroviral treatment (cART). In the cART era, the life expectancy of HIV-infected (HIV+) individuals has increased. More HIV+ individuals are aging with current projections suggesting that 50% of HIV+ individuals will be over 50 years old by 2015. With advancing age, HIV+ individuals may be at increased risk of developing other potential neurodegenerative disorders [especially Alzheimer’s disease (AD)]. Pathology studies have shown that HIV increases intra and possibly extracellular amyloid beta (Aβ42), a hallmark of AD. We review the synthesis and clearance of Aβ42 and the effects of HIV on the amyloid pathway, and contrast the impact of AD and HIV on Aβ42 metabolism. Biomarker studies (cerebrospinal fluid AB and amyloid imaging) in HIV+ have shown mixed results. CSF Aβ42 has been shown to be either normal or diminished in HIV+ patients with HIV associated neurocognitive disorders (HAND). Amyloid imaging using [11C] PiB has also not demonstrated increased extracellular amyloid fibrillar deposits in HAND patients. We further demonstrate that Aβ42 deposition is not increased in older HIV+ patients using [11C] PiB amyloid imaging. Together, these results suggest that HIV and aging each independently affect Aβ42 deposition with no significant interaction present. Older HIV+ patients are probably not at increased risk for developing AD. However, future longitudinal studies of older HIV+ patients using multiple modalities (including the combination of CSF markers and amyloid imaging) are necessary for investigating the effects of HIV on Aβ42 metabolism.

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Amyloid Precursor Proteins Interact with the Heterotrimeric G Protein Go in the Control of Neuronal Migration

Cited by 38 publications

References 99 publications

Cellular Functions of the Amyloid Precursor Protein from Development to Dementia

Cellular Functions of the Amyloid Precursor Protein from Development to Dementia

Amyloid Precursor Proteins Are Dynamically Trafficked and Processed during Neuronal Development

Role of HIV in Amyloid Metabolism

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