Clathrin adaptor AP-1–mediated Golgi export of amyloid precursor protein is crucial for the production of neurotoxic amyloid fragments

Januário, Yunan C; Eden, Jessica; Oliveira, Luan S de; Pace, Raffaella De; Tavares, Lucas Alves; Silva-Januário, Mara E. da; Apolloni, Vinícius B; Wilby, Elise L.; Altmeyer, Randolf; Burgos, Patricia V.; Corrêa, Sônia A.L.; Gershlick, David C.; daSilva, Luis L. P.

doi:10.1016/j.jbc.2022.102172

Cited by 8 publications

(12 citation statements)

References 67 publications

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“…By addition of biotin, mCherry-APP-EGFP was released from the hook and exported from the ER, followed by the arrival of mCherry-APP-EGFP at the Golgi, and finally localized to the plasma membrane and endolysosomal system. The observed mCherry-APP-EGFP intracellular localization is in accordance with endogenous APP and similar fluorescently tagged APP variants used in previous studies [8,41].…”

Section: Discussionsupporting

confidence: 88%

Inhibition of Autophagy Alters Intracellular Transport of APP Resulting in Increased APP Processing

Mayer,

Boeck,

Werner

et al. 2024

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Alzheimer's disease (AD) pathology is characterized by amyloid beta (Aβ) plaques and dysfunctional autophagy. Aβ is generated by sequential proteolytic cleavage of amyloid precursor protein (APP), and the site of intracellular APP processing is highly debated, which may include autophagosomes. Here, we investigated the involvement of autophagy, including the role of ATG9 in APP intracellular trafficking and processing by applying the RUSH system, which allows studying the transport of fluorescently labeled mCherry‐APP‐EGFP in a systematic way, starting from the endoplasmic reticulum. HeLa cells, expressing the RUSH mCherry‐APP‐EGFP system, were investigated by live cell imaging, immunofluorescence, and Western blot. We found that mCherry‐APP‐EGFP passed through the Golgi faster in ATG9 knockout cells. Furthermore, ATG9 deletion shifted mCherry‐APP‐EGFP from early endosomes and lysosomes toward the plasma membrane concomitant with reduced endocytosis. Importantly, this alteration in mCherry‐APP‐EGFP transport resulted in increased secreted mCherry‐soluble APP and C‐terminal fragment‐EGFP. These effects were also phenocopied by pharmacological inhibition of ULK1, indicating that autophagy is regulating the intracellular trafficking and processing of APP. These findings contribute to the understanding of the role of autophagy in APP metabolism and could potentially have implications for new therapeutic approaches for AD.

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Section: Discussionsupporting

confidence: 88%

Inhibition of Autophagy Alters Intracellular Transport of APP Resulting in Increased APP Processing

Mayer,

Boeck,

Werner

et al. 2024

Traffic

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“…Among the novel GW or SWS findings, SMAP2 encodes a GTPase‐activating protein (GAP) for Arf1 with a putative clathrin‐binding domain that binds the clathrin adaptor protein complex 1 (AP‐1) 35 . Clathrin adaptor AP‐1‐mediated Golgi export of amyloid precursor protein is crucial for the production of neurotoxic amyloid fragments 36 . Previous AD GWAS identified other genes in this pathway including PICALM and BIN1 37 .…”

Section: Discussionmentioning

confidence: 99%

“…35 Clathrin adaptor AP-1-mediated Golgi export of amyloid precursor protein is crucial for the production of neurotoxic amyloid fragments. 36 Previous AD GWAS identified other genes in this pathway including PICALM and BIN1. 37 RAB3B encodes one of four closely related small GTP-binding proteins (Rab3A, Rab3B, Rab3C, and Rab3D) that are believed to be involved in presynaptic vesicle trafficking and priming steps for regulating synaptic transmission and plasticity, an idea supported by patch-clamp electrophysiology experiments conducted in neuronal cultures from Rab3-deficient mouse hippocampus.…”

Section: Genementioning

confidence: 99%

Novel loci for Alzheimer's disease identified by a genome‐wide association study in Ashkenazi Jews

Farrell

Mez

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONMost Alzheimer's disease (AD) loci have been discovered in individuals with European ancestry (EA).METHODSWe applied principal component analysis using Gaussian mixture models and an Ashkenazi Jewish (AJ) reference genome‐wide association study (GWAS) data set to identify Ashkenazi Jews ascertained in GWAS (n = 42,682), whole genome sequencing (WGS, n = 16,815), and whole exome sequencing (WES, n = 20,504) data sets. The association of AD was tested genome wide (GW) in the GWAS and WGS data sets and exome wide (EW) in all three data sets (EW). Gene‐based analyses were performed using aggregated rare variants.RESULTSIn addition to apolipoprotein E (APOE), GW analyses (1355 cases and 1661 controls) revealed associations with TREM2 R47H (p = 9.66 × 10−9), rs541586606 near RAB3B (p = 5.01 × 10−8), and rs760573036 between SPOCK3 and ANXA10 (p = 6.32 × 10−8). In EW analyses (1504 cases and 2047 controls), study‐wide significant association was observed with rs1003710 near SMAP2 (p = 1.91 × 10−7). A significant gene‐based association was identified with GIPR (p = 7.34 × 10−7).DISCUSSIONOur results highlight the efficacy of founder populations for AD genetic studies.

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“…Genes encoding the BC2-CD8α-tagged NPxY , ΔMOTIF and TGN reporter constructs were obtained as synthetic DNA blocks (gBlocks; Integrated DNA Technologies), cloned into pHLSec via the AgeI-KpnI sites, and finally subcloned into modified PB-T PiggyBac cargo vectors (Halo-APP-mNeonGreen, (Januário et al, 2022 ), a gift from David Gershlick, University of Cambridge) via XbaI-KpnI sites such that the resultant reporter constructs are under the control of a constitutive chicken β-actin promoter (with CMV enhancer and chicken β-actin/rabbit β-globin chimeric intron) flanked by PiggyBac Transposase recognition sequences. Genes encoding the nanobodies αBC2 and αGFP were obtained as gBlocks (Integrated DNA Technologies) and subcloned into an in-house E. coli expression vector, pMW (Owen and Evans, 1998 ).…”

Section: Methodsmentioning

confidence: 99%

Repurposing an endogenous degradation domain for antibody-mediated disposal of cell-surface proteins

Schmitt,

Poole,

Groves

et al. 2024

EMBO Rep

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The exquisite specificity of antibodies can be harnessed to effect targeted degradation of membrane proteins. Here, we demonstrate targeted protein removal utilising a protein degradation domain derived from the endogenous human protein Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9). Recombinant antibodies genetically fused to this domain drive the degradation of membrane proteins that undergo constitutive internalisation and recycling, including the transferrin receptor and the human cytomegalovirus latency-associated protein US28. We term this approach PACTAC (PCSK9-Antibody Clearance-Targeting Chimeras).

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Clathrin adaptor AP-1–mediated Golgi export of amyloid precursor protein is crucial for the production of neurotoxic amyloid fragments

Cited by 8 publications

References 67 publications

Inhibition of Autophagy Alters Intracellular Transport of APP Resulting in Increased APP Processing

Inhibition of Autophagy Alters Intracellular Transport of APP Resulting in Increased APP Processing

Novel loci for Alzheimer's disease identified by a genome‐wide association study in Ashkenazi Jews

Repurposing an endogenous degradation domain for antibody-mediated disposal of cell-surface proteins

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