Hyperactivation of RAB5 disrupts the endosomal Rab cascade leading to endolysosomal dysregulation in Down syndrome: A necessary role for increased APP gene dose

Alzheimer s & Dementia, Год журнала: 2025, Номер 21(5)

Опубликована: Май 1, 2025

Abstract INTRODUCTION Down syndrome (DS) markedly increases the risk of Alzheimer's disease (DS‐AD), but role RAB5 hyperactivation in its pathogenesis remains unclear. METHODS Postmortem brain samples from individuals with DS, and without AD, a partial trisomy 21 case only two amyloid precursor protein ( APP ) gene copies, were examined for endosomal Rabs, their guanine‐nucleotide exchange factor (GEF) GTPase activating (GAP) levels, lysosomal cathepsins. Analysis extended to Dp16 DS mouse model. The disrupting endolysosomal system was explored using primary neurons. RESULTS We observed widespread dysregulation brains, requiring increased dose. resulted activation including RABs 7 11, recruitment Rabs GEFs early endosomes as well levels DISCUSSION These findings suggest that dose‐driven disrupts Rab cascades endosome maturation DS. Highlights There is disruption network model brain. Amyloid dose necessary activity cathepsins both human brains. Changes 11 linked factors (GEFs) GEF/GTPase ratios. Mechanistic studies demonstrated essential roles beta‐C‐terminal fragment (β‐CTF) acting through increase membrane binding downstream Rabs. acts central hub disruptions function

Язык: Английский

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Amyloid Precursor Protein: A Regulatory Hub in Alzheimer's Disease

Aging and Disease, Год журнала: 2023, Номер unknown

Опубликована: Янв. 1, 2023

Decades of research have demonstrated an incontrovertible role amyloid-β (Aβ) in the etiology Alzheimer's disease (AD). However, overemphasis on pathological impacts Aβ may obscure its metabolic precursor, amyloid precursor protein (APP), as a significant hub occurrence and progression AD. The complicated enzymatic processing, ubiquitous receptor-like properties, abundant expression APP brain, well close links with systemic metabolism, mitochondrial function neuroinflammation, imply that plays multifaceted roles In this review, we briefly describe evolutionarily conserved biological characteristics APP, including structure, functions processing. We also discuss possible involvement metabolites AD, both detrimental beneficial. Finally, pharmacological agents or genetic approaches capability to reduce inhibit cellular internalization, which can ameliorate multiple aspects AD pathologies halt progression. These provide basis for further drug development combat terrible disease.

Язык: Английский

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Impact of Cre/LoxP-Mediated Chromosome Engineering Technology on Down Syndrome Research

Опубликована: Янв. 1, 2025

Язык: Английский

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Antisense oligonucleotides directed against App and Rab5 normalized endosomal Rab activity and reversed DS‐AD‐linked degenerative phenotypes in the Dp16 mouse model of Down syndrome

Alzheimer s & Dementia, Год журнала: 2025, Номер 21(5)

Опубликована: Май 1, 2025

Abstract INTRODUCTION Down syndrome (DS) markedly raises the risk of Alzheimer's disease (DS‐AD). Our findings identified widespread dysregulation endolysosomal network (ELN) in DS and DS‐AD brains, driven by increased APP gene dose, hyperactivation RAB5, elevated levels guanine nucleotide exchange factors (GEFs) for RABs 7 11. METHODS We investigated whether increasing dose RAB5 contributed to neuropathogenesis a clinically feasible intervention could reverse ELN changes. The Dp16 mouse model was treated with App ‐specific antisense oligonucleotide ( ‐ASO) Rab5 ASOs targeting Rab5a Rab5b . RESULTS ‐ASO treatment normalized full‐length (fl‐APP) its products, activity, downstream 11 pathways. ‐ASOs reduced restored endosomal Rab activity. Both ASO treatments mitigated DS‐AD‐linked pathologies. DISCUSSION These highlight therapeutic potential ASO‐based strategies or counteract features. Highlights products activity GEF mice. Administration were well tolerated APP‐linked pathologies including tau hyperphosphorylation, neurotrophin signaling deficits, synaptic protein loss. reversed established pathological phenotypes

Язык: Английский

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Retromer Proteins Reduced in Down Syndrome and the Dp16 Model: Impact ofAPPDose and Preclinical Studies of a γ‐Secretase Modulator

Annals of Neurology, Год журнала: 2023, Номер 94(2), С. 245 - 258

Опубликована: Апрель 12, 2023

The retromer complex plays an essential role in intracellular endosomal sorting. Deficits the are linked to enhanced Aβ production. levels of components reported be downregulated Alzheimer disease (AD). Down syndrome (DS) shares neuropathological features with AD. Recent evidence points dysregulation DS. mechanisms underlying deficits DS and AD poorly understood.

Язык: Английский

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γ‐Secretase Modulator BPN15606 Reduced Aβ42 and Aβ40 and Countered Alzheimer‐Related Pathologies in a Mouse Model of Down Syndrome

Annals of Neurology, Год журнала: 2024, Номер 96(2), С. 390 - 404

Опубликована: Май 15, 2024

Objectives Due to increased gene dose for the amyloid precursor protein (APP), elderly adults with Down syndrome (DS) are at a markedly risk of Alzheimer's disease (AD), known as DS‐AD. How APP acts and which products responsible DS‐AD is not well understood, thus limiting strategies target pathogenesis. As one approach address this question, we used novel class γ‐secretase modulators that promote γ‐site cleavages by complex, resulting in lower levels Aβ42 Aβ40 peptides. Methods Ts65Dn mice, serve model DS, were treated via oral gavage 10 mg/kg/weekday BPN15606 (a potent pyridazine‐containing modulators). Treatment started 3 months‐of‐age lasted 4 months. Results Demonstrating successful engagement, treatment significantly decreased cortex hippocampus; it had no effect on full‐length or its C‐terminal fragments either 2 N mice. Importantly, total amyloid‐β impacted, pointing BPN15606‐mediated enhancement processivity γ‐secretase. Additionally, rescued hyperactivation Rab5, regulating endosome function, normalized neurotrophin signaling deficits. also synaptic proteins tau phosphorylation, while reducing astrocytosis microgliosis, countering cognitive Interpretation Our findings point involvement and/or contributing several molecular traits associated They speak dosage acting through heightened supporting These further interest potential use treating possibly preventing AD individuals DS. ANN NEUROL 2024;96:390–404

Язык: Английский

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Synapsin 1 Ameliorates Cognitive Impairment and Neuroinflammation in Rats with Alzheimer’s Disease: An Experimental and Bioinformatics Study

Current Alzheimer Research, Год журнала: 2023, Номер 20(9), С. 648 - 659

Опубликована: Сен. 1, 2023

Background::: Alzheimer’s disease (AD) is a persistent neuropathological injury that manifests via neuronal/synaptic death, age spot development, tau hyperphosphorylation, neuroinflammation, and apoptosis. Synapsin 1 (SYN1), neuronal phosphoprotein, believed to be responsible for the pathology of AD. Objective:: This study aimed elucidate exact role SYN1 in ameliorating AD its potential regulatory mechanisms. Methods:: The dataset GSE48350 was downloaded from GEO database, focused on differential expression analysis Gene Ontology (GO) Kyoto Encyclopedia Genes Genomes (KEGG) enrichment analyses. After establishing an rat model, they were treated with RNAi lentivirus trigger overexpression. amelioration AD-associated behavior validated using multiple experiments (water maze test object recognition test). SYN1’s repairing effect important factors confirmed by detecting concentration inflammatory (interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α), neurotransmitters (acetylcholine (ACh), dopamine (DA), 5-hydroxytryptophan (5-HT)) markers oxidative stress (glutathione (GSH), malondialdehyde (MDA), reactive oxygen species (ROS)). Molecular biology (qRT-PCR western blot) performed examine AD-related signaling pathways after Results:: Differential yielded total 545 differentially expressed genes, which four upregulated 541 downregulated. enriched basically synaptic functions, protein– protein interaction network key genes SYN1. significantly improved spatial learning memory abilities rats. enhancement reflected reduced escape latency rats water maze, extended dwell time third quadrant, increased number crossings. Furthermore, results revealed explore familiar new objects. overexpression, cAMP pathway activated, phosphorylation levels CREB PKA proteins elevated, secretion such as ACh, DA, 5-HT promoted. suppressed, supported decreased MDA ROS. Regarding factors, IL-6, TNF-α Conclusion:: overexpression improves cognitive function promotes release various inhibiting responses through activation. These findings may provide theoretical basis targeted diagnosis treatment

Язык: Английский

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Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome

Biological Research, Год журнала: 2023, Номер 56(1)

Опубликована: Дек. 9, 2023

Abstract Background Growing evidence has suggested that Type I Interferon (I-IFN) plays a potential role in the pathogenesis of Down Syndrome (DS). This work investigates underlying function MX1, an effector gene I-IFN, DS-associated transcriptional regulation and phenotypic modulation. Methods We performed assay for transposase-accessible chromatin with high-throughout sequencing (ATAC-seq) to explore difference accessibility between DS derived amniocytes (DSACs) controls. then combined annotated differentially expressed genes (DEGs) enriched factors (TFs) targeting promoter region from ATAC-seq results DEGs RNA-seq, identify key pathways involved alterations biological processes DS. Results Binding motif analysis showed significant increase related neural cell function, among others, DSACs, which is primarily regulated by members activator protein-1 (AP-1) factor family. Further studies indicated MX Dynamin Like GTPase 1 (MX1), defined as one critical upstream regulator. Its overexpression induced expression AP-1 TFs mediated inflammatory response, thus leading decreased cellular viability cells. Moreover, treatment specific inhibitor T-5224 improved phenotypes DSACs. Conclusions study demonstrates MX1-mediated activation partially responsible dysfunction effectively ameliorated suggesting it option patients.

Язык: Английский

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New insights into the effects of APP gene dose on synapse in Down syndrome

Neural Regeneration Research, Год журнала: 2023, Номер 19(5), С. 961 - 962

Опубликована: Авг. 14, 2023

Synaptic dysfunction: Alzheimer's disease (AD) is a prevalent form of dementia, affecting over 35 million people worldwide (Tzioras et al., 2023). A synapse serves as the connection point between neurons, facilitating transmission information from one neuron to another. Dynamic alterations in synapses, known synaptic plasticity, play pivotal role cognitive processes such learning and memory. loss has been identified key contributor decline AD patients. Studies have shown that soluble forms amyloid-beta (Aβ) tau proteins are toxic leading impairment animal models (Spires-Jones Hyman, 2014). Additionally, formation oligomers Aβ can spread pathology through connections brain, emphasizing vital synapses progression. Despite significance AD, effective treatments prevent or slow currently lacking. deeper understanding pathological changes could provide crucial biomarkers for early diagnosis treatment. Down syndrome (DS), trisomy 21, genetic disorder results an extra copy chromosome 21 part it. It most common cause intellectual developmental disabilities linked early-onset AD. Individuals with DS typically exhibit AD-like brain (DS-AD) by age 40, including amyloid plaques neurofibrillary tangles, which progress dementia 60 (Chen 2021). However, there limited research on DS-AD. Given similarities DS-AD pathology, it reasonable speculate individuals may also experience similar observed Amyloid precursor protein (APP) dose-dependent reduction DS: Neurotransmitter-containing vesicles release their contents into cleft, initiating neurons. Specific receptors postsynaptic then bind these neurotransmitters. The fusion plasma membrane requires N-ethylmaleimide-sensitive factor attachment receptor (SNARE) complex, composed vesicular SNARE synaptobrevin target syntaxin-1 synaptosomal-associated protein-25 (SNAP-25) (Sudhof, 2012). Changes core involved vesicle lead neurological dysfunction. Limited knowledge exists regarding levels distinctions While numerous reports investigated mild impairment, they uncovered inconsistent reductions various located both pre- post-synaptically. comparable underlying pathologies DS-AD, would be expected demonstrate alterations. Our revealed decreased several frontal cortex syntaxin 1A SNAP25, synaptophysin synapsin 1, well density PSD95. Notably, complex were correlated other 2023a), indicating essential necessary neurotransmitter signify dysfunction this set brains subjects consistent sporadic cases. no complexes patients without suggesting molecular cellular events defects jointly contribute potential pathogenesis comorbidities. Consistently, we notable age-dependent SNAP25 Dp16 mouse model. findings rare case partial (PT-DS) (Doran 2017) mice App gene normalization (Dp16: App++−) indicate increased dosage APP (Figure 1).Figure 1: Increased dose induces retromer subunits DS.Increased elevated its processing products, species. In but not diagnosis, dependent occurs, along complex. shows presynaptic compartments, DS, APP-dependent subunits. Aβ42 Aβ40 arising decrease subunit function, turn production. Thus, dosage-induced synergize affected pathways drive at different stages DS. Created BioRender.com. AD: disease; APP: protein; Aβ: amyloid-beta; syndrome; SNARE: receptor.Synaptic terminal contains only vesicles, variety components exocytosis endocytosis processes. One critical component responsible endosomal sorting. This recognizes specific transmembrane facilitates transport trans-Golgi network recycling back membrane. highlighted involvement neurodegenerative diseases, VPS26 VPS35 reduced. Dysfunction production Genetic studies retromer-associated SNX1, SNX3, Rab7a, SORL1/SORLA (Brodin Shupliakov, 2018). pathogenic mechanisms due expression upregulation microRNA miR-155 encoded found SNX27, resulting (Wang 2013). Moreover, hippocampal SNX27 improve deficits. Therefore, basis new strategies addressing loss. We significant VPS26A, VPS26B, VPS29 PT-DS 2023b). downregulation was 16-month-old dosage. GluA1 displayed same subunits, reflecting functions 1). To identify location isolated synaptosomes 20-month-old male 2N mice. enrichment each synaptosomes. throughout homogenate rather than cytoplasmic fraction. These suggest primary activity. Importantly, administration novel gamma-secretase modulator, designed specifically γ-site cleavages γ-secretase resulted levels, increase nontoxic Aβ38 Aβ37. treatment successfully restored VPS29, GluA1, diminished Limitations perspective: follow hierarchical pattern, function childhood young adulthood, followed AD-related neuronal later stages. latter characterized markers. worth highlighting particularly children adults, general abilities, attributed occurring brain. encompass deficits neurogenesis, maturation, synaptogenesis. strongly correlation modifications onset associated noteworthy comparatively less experiences comparison regions like entorhinal cortex. evaluate within vulnerable regions. Nevertheless, further investigations imperative ascertain whether present adults if so, elucidate changes. Furthermore, reported functional imbalance excitation inhibition, morphological enlargement spines, precise links electrophysiological features even behavioral outcomes need defined, although roles individual yet fully elucidated. Biomarkers utilized define status valuable investigate reflected corresponding body fluids. Further needed efficacy utilizing proteins, thereby enhancing our diagnostic tools. Contrarily, finding stands contrast obtained above, exhibited reduced DS-AS PT-DS. difference suggests while clinical differed. Rab5 activity characteristic feature demonstrated accelerate internalization endolysosomal system where C-terminal fragments species, (Grbovic 2003). retrieving endosomes membrane, process. accumulation detrimental effects stability consequently line this, impairs trafficking promotes cleavage β-secretase, Aβ, Aβ40. species creating positive feedback loop patterns start very stages, occur predominantly preclinical models, modulators extensively tested ability reduce making them promising therapeutic approach Gamma-secretase modulator study determine reverse proteins. Both transmission, evidenced models. still completely clear, how downstream synergistically microstructural changes, deficits, subsequent across Nonetheless, reinforce disrupting aligns requirement development C-Editors: Zhao M, Liu WJ, Qiu Y; T-Editor: Jia Y

Язык: Английский

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Deep Trans-Omic Network Fusion for Molecular Mechanism of Alzheimer’s Disease

Journal of Alzheimer s Disease, Год журнала: 2024, Номер 99(2), С. 715 - 727

Опубликована: Май 10, 2024

Background: There are various molecular hypotheses regarding Alzheimer’s disease (AD) like amyloid deposition, tau propagation, neuroinflammation, and synaptic dysfunction. However, detailed mechanism underlying AD remains elusive. In addition, genetic contribution of these hypothesis is not yet established despite the high heritability AD. Objective: The study aims to enable discovery functionally connected multi-omic features through novel integration data prior functional interactions. Methods: We propose a new deep learning model MoFNet with improved interpretability investigate its upstream contributors. integrates interactions between SNPs, genes, proteins, for first time models dynamic information flow from DNA RNA proteins. Results: When evaluated using ROS/MAP cohort, outperformed other competing methods in prediction performance. It identified proteins significantly more interactions, resulting three subnetworks. SNP-gene pairs by were mostly eQTLs specific frontal cortex tissue where gene/protein was collected. These subnetworks enriched innate immune system, clearance misfolded neurotransmitter release respectively. validated most findings an independent dataset. One subnetwork consists exclusively core members SNARE complex, key mediator vesicle fusion transportation. Conclusions: Our results suggest that effective improving classification accuracy identifying markers interpretability. Multi-omic provided insights details.

Язык: Английский

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