The Rab5 activator RME-6 is required for amyloid precursor protein endocytosis depending on the YTSI motif

Eggert, Simone; Gruebl, Tomas; Rajender, Ritu; Rupp, Carsten; Sander, Bianca; Heesch, Amelie; Zimmermann, Marius; Hoepfner, Sebastian; Zentgraf, Hanswalter; Kins, Stefan

doi:10.1007/s00018-020-03467-1

Cited by 8 publications

(13 citation statements)

References 76 publications

(105 reference statements)

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“…In contrast, detection with anti-c-myc antibodies demonstrated that higher amounts of APPΔCT were pulled down via trans -coimmunoprecipitation compared with APP WT (Figure 4B) . This demonstrates that indeed, a higher presence of APP at the cell surface due to strongly impaired endocytosis (Eggert et al, 2020) goes along with a higher amount of APP trans -dimers.…”

Section: Resultsmentioning

confidence: 84%

“…It has been reported that APP seems to be almost completely dimerized at the cell surface and involves the presence of heparan sulfate at the plasma membrane (Gralle et al, 2009). Surface localization of APP is a balance from its transport in the secretory path, its internalization and its processing (Eggert et al, 2018a; Eggert et al, 2020; Eggert et al, 2022; Eggert et al, 2018b). For example, reduced proteolysis of APP in processing deficient mutants leads to an increased surface localization of APP, resulting in elevated trans -dimerization and synapse formation (Stahl et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…For example, reduced proteolysis of APP in processing deficient mutants leads to an increased surface localization of APP, resulting in elevated trans -dimerization and synapse formation (Stahl et al, 2014). APP internalization from the cell surface occurs predominantly by Clathrin mediated endocytosis via the NPTY motif in the C-terminus of APP (Eggert et al, 2020; Koo and Squazzo, 1994), but also via the basolateral Sorting sequence (BaSS) of APP which is the YTSI motif C-terminal of the transmembrane domain (Eggert et al, 2020; Lai et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

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„APP family member dimeric complexes are formed predominantly in synaptic compartments“

Schilling

August

Meleux

et al. 2022

Preprint

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The amyloid precursor protein (APP), a key player in Alzheimer's disease (AD), is part of a larger gene family, including the APP like proteins APLP1 and APLP2. They share similar structures, form homo- and heterotypic dimers and exhibit overlapping functions. We investigated complex formation of the APP family members via two inducible dimerization systems, the FKBP-rapamycin based dimerization as well as cysteine induced dimerization, combined with coimmunoprecipitations and Blue Native (BN) gel analyses. Within the APP family, APLP1 shows the highest degree of dimerization and high molecular weight (HMW) complex formation. Interestingly, about 20% of APP is dimerized in cultured cells while about 50% of APP is dimerized in mouse brains, independent of age and splice forms. Furthermore, we could show that dimerized APP originates mostly from neurons and is enriched in synaptosomes. Finally, BN gel analysis of human cortex samples shows a significant decrease of APP dimers in AD patients compared to controls, suggesting that loss of dimers of full-length APP might correlate with loss of synapses in the process of AD.

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Section: Resultsmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

„APP family member dimeric complexes are formed predominantly in synaptic compartments“

Schilling

August

Meleux

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…The amyloid cascade hypothesis suggests that Aβ plaques accumulate in the brain, leading to neurodegeneration and even cell death. The breakdown of APP depends on three different secretases (α‐, β‐, and γ‐) (Eggert et al, 2020). In the nonamyloidosis pathway, full‐length APP is cleaved by α‐ and γ‐secretase to produce nonneurotoxic fragments (Yeung et al, 2019).…”

Section: Alzheimerʼs Disease and Ferroptosismentioning

confidence: 99%

“…(α-, β-, and γ-)(Eggert et al, 2020). In the nonamyloidosis pathway, full-length APP is cleaved by α-and γ-secretase to produce nonneurotoxic fragments(Yeung et al, 2019).…”

mentioning

confidence: 99%

The key roles of organelles and ferroptosis in Alzheimerʼs disease

Long

Cheng

Zhou

et al. 2022

J of Neuroscience Research

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Alzheimerʼs disease (AD), an age-related neurodegenerative disease, is a striking global health problem. Ferroptosis is a newly discovered form of cell death characterized by iron-dependent lipid peroxidation products and the accumulation of lethal reactive oxygen species. Strict regulation of iron metabolism is essential to ensure neuronal homeostasis. Excess and deficiency of iron are both associated with neurodegeneration.Studies have shown that oxidative stress caused by cerebral iron metabolism disorders in the body is involved in the process of AD, ferroptosis may play an important role in the pathogenesis of AD, and regulating ferroptosis is expected to be a new direction for the treatment of AD. Various organelles are closely related to ferroptosis: mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosome are involved in the regulation of ferroptosis from the aspects of iron metabolism and redox imbalance. In this review, the relationship between AD and the dysfunction of organelles (including mitochondria, endoplasmic reticulum, lysosome, and Golgi apparatus) and the role of organelles in ferroptosis of AD were reviewed to provide insights for understanding the relationship between organelles and ferroptosis in AD and the treatment of AD.

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Endocytosis and Alzheimer’s disease

Zadka,

Sochocka,

Hachiya

et al. 2023

GeroScience

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia. The pathogenesis of AD still remains unclear, including two main hypotheses: amyloid cascade and tau hyperphosphorylation. The hallmark neuropathological changes of AD are extracellular deposits of amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Endocytosis plays an important role in a number of cellular processes including communication with the extracellular environment, nutrient uptake, and signaling by the cell surface receptors. Based on the results of genetic and biochemical studies, there is a link between neuronal endosomal function and AD pathology. Taking this into account, we can state that in the results of previous research, endolysosomal abnormality is an important cause of neuronal lesions in the brain. Endocytosis is a central pathway involved in the regulation of the degradation of amyloidogenic components. The results of the studies suggest that a correlation between alteration in the endocytosis process and associated protein expression progresses AD. In this article, we discuss the current knowledge about endosomal abnormalities in AD.

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The Rab5 activator RME-6 is required for amyloid precursor protein endocytosis depending on the YTSI motif

Cited by 8 publications

References 76 publications

„APP family member dimeric complexes are formed predominantly in synaptic compartments“

„APP family member dimeric complexes are formed predominantly in synaptic compartments“

The key roles of organelles and ferroptosis in Alzheimerʼs disease

Endocytosis and Alzheimer’s disease

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