ArticleMolecular psychiatry2022
APP and DYRK1A regulate axonal and synaptic vesicle protein networks and mediate Alzheimer's pathology in trisomy 21 neurons.
Article in Molecular psychiatry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 32 citations in OpenAlex.
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- Leucettinib-21 decreases dosage effects of DYRK1A in human trisomy 21 induced pluripotent stem cell-derived neural cells.Disease models & mechanisms · 2026Article
- Amyloid precursor protein dosage normalization rescues neurogenesis and Alzheimer's Disease phenotypes associated with Down Syndrome.Medical research archives · 2026Article
- Targeting DNA damage in ageing: towards supercharging DNA repair.Nature reviews. Drug discovery · 2025Review
- Astrocyte induction of disease-associated microglia is suppressed by acute exposure to fAD neurons in human iPSC triple cultures.Cell reports · 2025Article
- Identification of therapeutic targets for Alzheimer's Disease Treatment using bioinformatics and machine learning.Scientific reports · 2025Article
- Analysis of genotype effects and inter-individual variability in iPSC-derived trisomy 21 neural progenitor cells.Human molecular genetics · 2025Article
- DYRK1A in the physiology and pathology of the neuron-astrocyte axis.Frontiers in neuroscience · 2025Review
- Identification of novel risk genes for Alzheimer's disease by integrating genetics from hippocampus.Scientific reports · 2024Article
- In and out: Benchmarking in vitro, in vivo, ex vivo, and xenografting approaches for an integrative brain disease modeling pipeline.Stem cell reports · 2024Review
- A stem cell-based assay platform demonstrates alpha-synuclein dependent synaptic dysfunction in patient-derived cortical neurons.NPJ Parkinson's disease · 2024Article
- Identification of novel hub genes for Alzheimer's disease associated with the hippocampus using WGCNA and differential gene analysis.Frontiers in neuroscience · 2024Article
- Serum proteomic biomarker investigation of vascular depression using data-independent acquisition: a pilot study.Frontiers in aging neuroscience · 2024Article
- Article
- Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels.EBioMedicine · 2023Article
- Moving beyond amyloid and tau to capture the biological heterogeneity of Alzheimer's disease.Trends in neurosciences · 2023Review
- Increased plasma DYRK1A with aging may protect against neurodegenerative diseases.Translational psychiatry · 2023Article
- Review
- Network pharmacology and molecular docking of endogenous active metabolites in diabetic kidney disease.Renal failure · 2023Article
- Consequences of chromosome gain: A new view on trisomy syndromes.American journal of human genetics · 2022Review
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
Abstract
Trisomy 21 (T21) causes Down syndrome and an early-onset form of Alzheimer's disease (AD). Here, we used human induced pluripotent stem cells (hiPSCs) along with CRISPR-Cas9 gene editing to investigate the contribution of chromosome 21 candidate genes to AD-relevant neuronal phenotypes. We utilized a direct neuronal differentiation protocol to bypass neurodevelopmental cell fate phenotypes caused by T21 followed by unbiased proteomics and western blotting to define the proteins dysregulated in T21 postmitotic neurons. We show that normalization of copy number of APP and DYRK1A each rescue elevated tau phosphorylation in T21 neurons, while reductions of RCAN1 and SYNJ1 do not. To determine the T21 alterations relevant to early-onset AD, we identified common pathways altered in familial Alzheimer's disease neurons and determined which of these were rescued by normalization of APP and DYRK1A copy number in T21 neurons. These studies identified disruptions in T21 neurons in both the axonal cytoskeletal network and presynaptic proteins that play critical roles in axonal transport and synaptic vesicle cycling. These alterations in the proteomic profiles have functional consequences: fAD and T21 neurons exhibit dysregulated axonal trafficking and T21 neurons display enhanced synaptic vesicle release. Taken together, our findings provide insights into the initial molecular alterations within neurons that ultimately lead to synaptic loss and axonal degeneration in Down syndrome and early-onset AD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.