Rab5 Mediates an Amyloid Precursor Protein Signaling Pathway That Leads to Apoptosis

Laifenfeld, Daphna; Patzek, Lucas J.; McPhie, Donna L.; Chen, Yuzhi; Levites, Yona; Cataldo, Anne M.; Neve, Rachael L.

doi:10.1523/jneurosci.4599-06.2007

Cited by 59 publications

(62 citation statements)

References 63 publications

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“…Such studies are worthwhile in particular in light of the genetic association of late-onset AD with the neuronal sortilin-related receptor, Sorl1, a protein involved in the regulation of the endosomal trafficking of APP (Spoelgen et al, 2006;Rogaeva et al, 2007) and the known endocytic pathway abnormalities in Alzheimer's disease (Cataldo et al, 2003;Nixon, 2005;Laifenfeld et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Flotillin-Dependent Clustering of the Amyloid Precursor Protein Regulates Its Endocytosis and Amyloidogenic Processing in Neurons

et al. 2008

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The flotillins/reggie proteins are associated with noncaveolar membrane microdomains and have been implicated in the regulation of a clathrin-and caveolin-independent endocytosis pathway. Endocytosis is required for the amyloidogenic processing of the amyloid precursor protein (APP) and thus to initiate the release of the neurotoxic ␤-amyloid peptide (A␤), the major component of extracellular plaques found in the brains of Alzheimer's disease patients. Here, we report that small interference RNA-mediated downregulation of flotillin-2 impairs the endocytosis of APP, in both neuroblastoma cells and primary cultures of hippocampal neurons, and reduces the production of A␤. Similar to tetanus neurotoxin endocytosis, but unlike the internalization of transferrin, clathrin-dependent endocytosis of APP requires cholesterol and adaptor protein-2 but is independent of epsin1 function. Moreover, on a nanoscale resolution using stimulated emission depletion microscopy and by Förster resonance energy transfer with fluorescence lifetime imaging microscopy, we provide evidence that flotillin-2 promotes the clustering of APP at the cell surface. We show that the interaction of flotillin-2 with APP is dependent on cholesterol and that clustering of APP enhances its endocytosis rate. Together, our data suggest that cholesterol/flotillindependent clustering of APP may stimulate the internalization into a specialized clathrin-dependent endocytosis pathway to promote amyloidogenic processing.

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Section: Discussionmentioning

confidence: 99%

Flotillin-Dependent Clustering of the Amyloid Precursor Protein Regulates Its Endocytosis and Amyloidogenic Processing in Neurons

et al. 2008

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“…It is this abnormal rab5 activation that causes protein and lipid accumulation in endosomes, slowed lysosomal degradation of endocytic cargoes, endosome swelling , and disrupted retrograde transport of endosomes (S Kim and RA Nixon, unpubl.). Interactions between FAD-mutant forms of APP and APP binding protein (APP-BP1) on endosomes also initiate pathological rab5 activation, which was shown to promote a neuronal apoptosis cascade (Laifenfeld et al 2007).…”

Section: Ad Genetics Implicates the Lysosomal Network In Pathogenesismentioning

confidence: 99%

The Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease

Ihara¹,

Morishima-Kawashima²,

Nixon³

2012

Cold Spring Harbor Perspectives in Medicine

153

126

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As neurons age, their survival depends on eliminating a growing burden of damaged, potentially toxic proteins and organelles-a capability that declines owing to aging and disease factors. Here, we review the two proteolytic systems principally responsible for protein quality control in neurons and their important contributions to Alzheimer disease pathogenesis. In the first section, the discovery of paired helical filament ubiquitination is described as a backdrop for discussing the importance of the ubiquitin-proteasome system in Alzheimer disease. In the second section, we review the prominent involvement of the lysosomal system beginning with pathological endosomal-lysosomal activation and signaling at the very earliest stages of Alzheimer disease followed by the progressive failure of autophagy. These abnormalities, which result in part from Alzheimer-related genes acting directly on these lysosomal pathways, contribute to the development of each of the Alzheimer neuropathological hallmarks and represent a promising therapeutic target.

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“…APP-BP1 was first cloned as an APP-interacting protein in 1996 and has been shown to play a role in activating the neddylation pathway through its binding with Uba3 [22,33,34]. However, APP-BP1 was recently shown to enhance receptor-mediated endocytosis in neurons in a neddylation-independent manner [24].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, overexpression of APP-BP1 in primary cortical neurons has been reported to increase Rab5-mediated endocytosis, in an APP binding dependent manner [24]. Endocy-tosis has been linked to the cell cycle [25].…”

Section: Introductionmentioning

confidence: 99%

Amyloid Precursor Protein Binding Protein-1 Is Up-regulated in Brains of Tg2576 Mice

Yang

Joo

Hong

et al. 2010

Korean J Physiol Pharmacol

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Amyloid precursor protein binding protein-1 (APP-BP1) binds to the carboxyl terminus of amyloid precursor protein and serves as a bipartite activation enzyme for the ubiquitin-like protein, NEDD8. Previously, it has been reported that APP-BP1 rescues the cell cycle S-M checkpoint defect in Ts41 hamster cells, that this rescue is dependent on the interaction of APP-BP1 with hUba3. The exogenous expression of APP-BP1 in neurons has been reported to cause DNA synthesis and apoptosis via a signaling pathway that is dependent on APP-BP1 binding to APP. These results suggest that APP-BP1 overexpression contributes to neurodegeneration. In the present study, we explored whether APP-BP1 expression was altered in the brains of Tg2576 mice, which is an animal model of Alzheimer's disease. APP-BP1 was found to be up-regulated in the hippocampus and cortex of 12 month-old Tg2576 mice compared to age-matched wild-type mice. In addition, APP-BP1 knockdown by siRNA treatment reduced cullin-1 neddylation in fetal neural stem cells, suggesting that APP-BP1 plays a role in cell cycle progression in the cells. Collectively, these results suggest that increased expression of APP-BP1, which has a role in cell cycle progression in neuronal cells, contributes to the pathogenesis of Alzheimer's disease.

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Rab5 Mediates an Amyloid Precursor Protein Signaling Pathway That Leads to Apoptosis

Cited by 59 publications

References 63 publications

Flotillin-Dependent Clustering of the Amyloid Precursor Protein Regulates Its Endocytosis and Amyloidogenic Processing in Neurons

Flotillin-Dependent Clustering of the Amyloid Precursor Protein Regulates Its Endocytosis and Amyloidogenic Processing in Neurons

The Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease

Amyloid Precursor Protein Binding Protein-1 Is Up-regulated in Brains of Tg2576 Mice

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