The apolipoprotein receptor LRP3 compromises APP levels

Cuchillo-Ibáñez, Inmaculada; Lennol, Matthew P.; Escamilla, Sergio; Mata-Balaguer, Trinidad; Valverde-Vozmediano, Lucía; López-Font, Inmaculada; Ferrer, Isidro; Sáez‐Valero, Javier

doi:10.1186/s13195-021-00921-5

Cited by 9 publications

(7 citation statements)

References 75 publications

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“…Of the up-regulated transcripts, 612 are augmented by both Apoer2-ICDs, 49 by Apoer2-ICD[+19], and 57 by Apoer2-ICD[Δ19]. One of the transcripts up-regulated by only the Apoer2-ICD[+19] is LRP3, whose expression is increased by Apoer2 and is reduced in the frontal cortex of postmortem AD brains [ 19 ]. The top functional enrichment categories for these up-regulated transcripts were post-synapse, cell junction organization, and cellular component morphogenesis (Figure S 5 A, Table S 6 ).…”

Section: Resultsmentioning

confidence: 99%

Regulation of the hippocampal translatome by Apoer2-ICD release

Wasser,

Werthmann,

Hall

et al. 2023

Mol Neurodegeneration

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Background ApoE4, the most significant genetic risk factor for late-onset Alzheimer’s disease (AD), sequesters a pro-synaptogenic Reelin receptor, Apoer2, in the endosomal compartment and prevents its normal recycling. In the adult brain, Reelin potentiates excitatory synapses and thereby protects against amyloid-β toxicity. Recently, a gain-of-function mutation in Reelin that is protective against early-onset AD has been described. Alternative splicing of the Apoer2 intracellular domain (Apoer2-ICD) regulates Apoer2 signaling. Splicing of juxtamembraneous exon 16 alters the γ-secretase mediated release of the Apoer2-ICD as well as synapse number and LTP, and inclusion of exon 19 ameliorates behavioral deficits in an AD mouse model. The Apoer2-ICD has also been shown to alter transcription of synaptic genes. However, the role of Apoer2-ICD release upon transcriptional regulation and its role in AD pathogenesis is unknown. Methods To assess in vivo mRNA-primed ribosomes specifically in hippocampi transduced with Apoer2-ICD splice variants, we crossed wild-type, cKO, and Apoer2 cleavage-resistant mice to a Cre-inducible translating ribosome affinity purification (TRAP) model. This allowed us to perform RNA-Seq on ribosome-loaded mRNA harvested specifically from hippocampal cells transduced with Apoer2-ICDs. Results Across all conditions, we observed ~4,700 altered translating transcripts, several of which comprise key synaptic components such as extracellular matrix and focal adhesions with concomitant perturbation of critical signaling cascades, energy metabolism, translation, and apoptosis. We further demonstrated the ability of the Apoer2-ICD to rescue many of these altered transcripts, underscoring the importance of Apoer2 splicing in synaptic homeostasis. A variety of these altered genes have been implicated in AD, demonstrating how dysregulated Apoer2 splicing may contribute to neurodegeneration. Conclusions Our findings demonstrate how alternative splicing of the APOE and Reelin receptor Apoer2 and release of the Apoer2-ICD regulates numerous translating transcripts in mouse hippocampi in vivo. These transcripts comprise a wide range of functions, and alterations in these transcripts suggest a mechanistic basis for the synaptic deficits seen in Apoer2 mutant mice and AD patients. Our findings, together with the recently reported AD-protective effects of a Reelin gain-of-function mutation in the presence of an early-onset AD mutation in Presenilin-1, implicate the Reelin/Apoer2 pathway as a target for AD therapeutics. Graphical Abstract

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Section: Resultsmentioning

confidence: 99%

Regulation of the hippocampal translatome by Apoer2-ICD release

Wasser,

Werthmann,

Hall

et al. 2023

Mol Neurodegeneration

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“…Previous research had found that 200 μM of Al(mal) 3 -exposed PC12 cells after 12 h and 24 h resulted in a significant increase in the Aβ 42 protein content of PC12 cells and a significant decrease in the Aβ 40 protein content. Reelin and Dab1 expression levels also changed during Aβ metabolism (Cuchillo-Ibanez et al, 2021; Thordardottir et al, 2017). Reelin can inhibit the APP amyloid hydrolysis pathway; on the other hand, it can promote the interaction between Dab1 and APP, and inhibit the generation of toxic Aβ.…”

Section: Discussionmentioning

confidence: 99%

Effect of the Reelin-Dab1 signaling pathway on the abnormal metabolism of Aβ protein induced by aluminum

et al. 2023

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Aluminum (Al) is a common neurotoxic element that can exacerbate intracellular β-amyloid (Aβ) deposition. Reelin is a highly conserved extracellular glycoprotein that is involved in intracellular Aβ deposition. However, the action of Reelin on aluminum-induced Aβ deposition is not fully understood. Here, we investigated the effects of the Reelin-Dab1 signaling pathway on Aβ deposition in aluminum maltol (Al(mal)3) exposure in rat pheochromocytoma-derived cells (PC12). Our results showed that Al(mal)3 exposure decreased activity of PC12, increased expression of Aβ42, and decreased expression of Aβ40. Moreover, Al(mal)3 exposure in PC12 induced Reelin-Dab1 signaling pathway-associated proteins changed, decreased expression of Reelin and Dab1, and increased expression of pdab1. Moreover, the expression of Reelin, Dab1, and Aβ40 was found to be elevated in PC12 exposed to Al(mal)3 and corticosterone compared to those exposed to Al(mal)3. Also, the expression of Reelin, Dab1, and Aβ40 was found to be depressed in PC12 exposed to Al(mal)3 and streptozotocin compared with cells exposed to Al(mal)3 alone. These results suggested that Al(mal)3 inhibits the expression of the Reelin-Dab1 signaling pathway, promoting Aβ deposition. Thus, our findings provided important evidence to better understand how the Reelin-Dab1 signaling pathway may be a potential mechanism of Aβ deposition induced by aluminum.

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“…The first was LDL receptor related protein 8 ( LRP8 ), AS of which is associated with Braak stage in both regions. It is a member of the LDL receptor family and performs key functions in brain development by affecting synaptic plasticity, allowing lipoprotein trafficking, and promoting cell development [ 34 ]. Also, it is involved in APP processing and Aβ secretion, and hence plays a significant role in AD pathogenesis and neurodegeneration [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…It is a member of the LDL receptor family and performs key functions in brain development by affecting synaptic plasticity, allowing lipoprotein trafficking, and promoting cell development [ 34 ]. Also, it is involved in APP processing and Aβ secretion, and hence plays a significant role in AD pathogenesis and neurodegeneration [ 34 ]. Notably, previous studies have demonstrated that LRP8 mRNA splicing alterations are correlated with AD progression through remodeling LRP8 functions [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Brain Region-Dependent Alternative Splicing of Alzheimer Disease (AD)-Risk Genes Is Associated With Neuropathological Features in AD

Kim¹,

Han²,

Cho³

et al. 2022

Int Neurourol J

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Purpose: Alzheimer disease (AD) is one of the most complex diseases and is characterized by AD-related neuropathological features, including accumulation of amyloid-β plaques and tau neurofibrillary tangles. Dysregulation of alternative splicing (AS) contributes to these features, and there is heterogeneity in features across brain regions between AD patients, leading to different severity and progression rates; however, brain region-specific AS mechanisms still remain unclear. Therefore, we aimed to systemically investigate AS in multiple brain regions of AD patients and how they affect clinical features.Methods: We analyzed RNA sequencing (RNA-Seq) data obtained from brain regions (frontal and temporal) of AD patients. Reads were mapped to the hg19 reference genome using the STAR aligner, and exon skipping (ES) rates were estimated as percent spliced in (PSI) by rMATs. We focused on AD-risk genes discovered by genome-wide association studies, and accordingly evaluated associations between PSI of skipped exons in AD-risk genes and Braak stage and plaque density mean (PM) for each brain region. We also integrated whole-genome sequencing data of the ascertained samples with RNA-Seq data to identify genetic regulators of feature-associated ES.Results: We identified 26 and 41 ES associated with Braak stage in frontal and temporal regions, respectively, and 10 and 50 ES associated with PM. Among those, 10 were frontal-specific (CLU and NTRK2), 65 temporal-specific (HIF1A and TRPC4AP), and 26 shared ES (APP) that accompanied functional Gene Ontology terms, including axonogenesis in shared-ES genes. We further identified genetic regulators that account for 44 ES (44% of the total). Finally, we present as a case study the systematic regulation of an ES in APP, which is important in AD pathogenesis.Conclusions: This study provides new insights into brain region-dependent AS regulation of the architecture of AD-risk genes that contributes to AD pathologies, ultimately allowing identification of a treatment target and region-specific biomarkers for AD.

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The apolipoprotein receptor LRP3 compromises APP levels

Cited by 9 publications

References 75 publications

Regulation of the hippocampal translatome by Apoer2-ICD release

Regulation of the hippocampal translatome by Apoer2-ICD release

Effect of the Reelin-Dab1 signaling pathway on the abnormal metabolism of Aβ protein induced by aluminum

Brain Region-Dependent Alternative Splicing of Alzheimer Disease (AD)-Risk Genes Is Associated With Neuropathological Features in AD

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