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Cited by 5Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchAmyotrophic Lateral Sclerosis Research

The DOI matches its Crossref record; 93 of the 94 references it cites were found in a registry or an index, and 1 are not checked yet; none of the 20 sources its claims cite is checked for support yet.

Multi-omic phenotyping of MAPT V337M neurons reveals early changes in axonogenesis and tau phosphorylation

Open access
Mohl, Gregory A., Dixon, Gary, Marzette, Emily, McKetney, Justin, Samelson, Avi J., Serras, Carlota Pereda, Jin, Julianne, Ariqat, Nabeela, Keys, Andrea, Chavira, Cristian, Li, Andrew, Boggess, Steven C., Swaney, Danielle L., Kampmann, Martin·2026·npj Dementia
DOI 10.1038/s44400-026-00076-wPMC PMC13110130

Published version of a preprint

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Abstract

Tau aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer’s disease and frontotemporal dementia. There are disease-causing variants of the tau-encoding gene, MAPT , and the presence of tau aggregates is highly correlated with disease progression. However, the molecular mechanisms linking pathological tau to neuronal dysfunction are not well understood. This is in part due to an incomplete understanding of the normal functions of tau in development and aging, and how the associated molecular and cellular processes change in the context of causal disease variants of tau. To address these questions in an unbiased manner, we conducted multi-omic characterization of iPSC-derived neurons harboring the MAPT V337M mutation or MAPT knockdown. RNA-seq, ATAC-seq, and phosphoproteomics revealed that both the V337M mutation and tau knockdown perturbed levels of transcripts and phosphorylation of proteins related to axonogenesis or axon morphology. When we directly measured axonogenesis, we found that both MAPT V337M and MAPT knockdown caused decreased axon length. Surprisingly, we found that neurons with V337M tau had much lower tau phosphorylation than neurons with WT tau. CRISPR-based screens uncovered regulators of tau phosphorylation in neurons and found that factors involved in axonogenesis modified tau phosphorylation in both MAPT WT and MAPT V337M neurons. Intriguingly, the p38 MAPK pathway specifically modified tau phosphorylation in MAPT V337M neurons. We propose that V337M tau perturbs tau phosphorylation and axon morphology pathways that are relevant to the normal function of tau in development, which could contribute to previously reported cognitive changes in preclinical MAPT variant carriers.

Checked 2026-11-13 · 1 reference not checked yet

Overview

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TL;DR

Multi-omic profiling of iPSC-derived neurons with the FTD-causing MAPT V337M mutation or tau knockdown reveals overlapping early perturbations in axonogenesis pathways and unexpectedly lower tau phosphorylation. The authors propose that V337M tau perturbs normal tau functions during development, with p38 MAPK specifically linked to tau phosphorylation in mutant neurons.

Key findings

  • RNA-seq, ATAC-seq, and phosphoproteomics showed that MAPT V337M and tau knockdown both perturb axonogenesis-related transcripts, chromatin accessibility, and protein phosphorylation; AP-1/cJun motifs were more accessible, and cJun/p-cJun were increased in mutant neurons.
  • Direct imaging of day 5 neurons found that both MAPT V337M and MAPT knockdown decreased main axon length and total neurite length, without significantly perturbing axon branch or secondary neurite length.
  • V337M tau was hypophosphorylated at one week of differentiation across many sites, including pS202/pT205 by AT8, and this was transient, approaching WT levels by two to four weeks; overexpressed V337M tau, but not WT or R406W tau, recapitulated lower phosphorylation.
  • CRISPR screens targeting 2,325 genes found cytoskeleton and neuron projection development regulators of tau phosphorylation in both MAPT WT and MAPT V337M neurons, while the p38 MAPK pathway specifically modified tau phosphorylation in MAPT V337M neurons.

Methods

  • Human iPSC lines from WTC11 and GIH6C1 backgrounds were edited to generate isogenic MAPT WT, heterozygous V337M, and homozygous V337M neurons, with doxycycline-inducible Ngn2 differentiation and CRISPRi/a machinery for tau knockdown or screens.
  • The study combined bulk RNA-seq at 2 and 4 weeks, ATAC-seq at 2 and 4 weeks, total proteomics and phosphoproteomics at 1 week, longitudinal live imaging of axonogenesis at day 5, western blots, in vitro phosphorylation assays with GSK3B and PKA, and pooled CRISPRi/a screens using an AT8-based FACS readout.
  • Analyses included DESeq2 for RNA-seq/ATAC-seq, MACS2 and chromVAR for chromatin, Spectronaut/MSstats for proteomics, Enrichr for gene set enrichment, and MAGeCK-iNC for CRISPR screens.

Limitations

  • The paper states that the neurons only express the fetal tau isoform 0N3R under the conditions used, that the study lacks mechanistic insight into how V337M causes tau loss of function, and that different disease variants of tau may have different effects.
  • Evident from the text: findings are from iPSC-derived Ngn2 neurons at early differentiation timepoints, and the tau hypophosphorylation phenotype is transient, so relevance to mature neurons or aging/disease stages is not established.
  • Evident from the text: the CRISPR screens used the AT8 antibody for pS202/pT205 and a druggable genome library, so regulators of other tau phosphosites or non-druggable genes may be missed.

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Crossref · 10.1038/s44400-026-00076-w

Cites

93 of 94 references verified0 citation errors · 0 not checkable

Statistics

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Figures

Fig. 1 RNA-seq and ATAC-seq in neurons reveal conserved effects of MAPT V337M and MAPT knockdown on axonogenesis pathways. A iPSCs from a healthy donor (WTC11, here called MAPT WT) or a patient with the heterozygous MAPT V337M mutation (GIH6C1, here called *MAPT Het) were edited with Cas9 previously to generate a heterozygous MAPT V337M clone (MAPT Het), a homozygous MAPT V337M clone (MAPT Hom), and a healthy isogenic control (GIH6C1∆1E11, here called *MAPT WT). These cells were engineered to express dox-inducible mNGN2 in AAVS1 and CRISPRi machinery in CLYBL. We transduce the iPSCs with lentivirus for sgRNA/BFP expression. B Heatmap comparing changes in gene expression based on RNA-seq in MAPT Het NTC and MAPT WT MAPT KD vs. MAPT WT NTC at 2 and 4 weeks post differentiation. Three independent wells of neurons for each genotype/sgRNA combination were harvested at each time point. C Gene Ontology (GO) term enrichment analysis of the RNA-seq experiment in (B). Genes that are differentially expressed in both MAPT Het and MAPT WT MAPT KD vs. MAPT WT NTC were analyzed with Enrichr, and top terms were plotted. Pathways related to axonogenesis and neuron morphology are colored magenta. D Heatmap summarizing ATAC-seq differential peaks at 4 weeks of differentiation. Two independent wells of neurons for each genotype/sgRNA combination were harvested. E Heatmap summarizing ATAC-seq transcription factor motif analysis at 4 weeks of differentiation from the same experiment in (D). Clusters were analyzed for pathway enrichment using Enrichr, and major pathways are annotated (“AP-1 Transcription Factor Network” and “Neuron Differentiation”). Quantification of cJun (F) and p-cJun (G) from the western blots in (S2D). Significance was calculated using one-way ANOVA with Šidák’s multiple comparison test, and comparisons were restricted within the donor background.
Fig. 1 RNA-seq and ATAC-seq in neurons reveal conserved effects of MAPT V337M and MAPT knockdown on axonogenesis pathways. A iPSCs from a healthy donor (WTC11, here called MAPT WT) or a patient with the heterozygous MAPT V337M mutation (GIH6C1, here called *MAPT Het) were edited with Cas9 previously to generate a heterozygous MAPT V337M clone (MAPT Het), a homozygous MAPT V337M clone (MAPT Hom), and a healthy isogenic control (GIH6C1∆1E11, here called *MAPT WT). These cells were engineered to express dox-inducible mNGN2 in AAVS1 and CRISPRi machinery in CLYBL. We transduce the iPSCs with lentivirus for sgRNA/BFP expression. B Heatmap comparing changes in gene expression based on RNA-seq in MAPT Het NTC and MAPT WT MAPT KD vs. MAPT WT NTC at 2 and 4 weeks post differentiation. Three independent wells of neurons for each genotype/sgRNA combination were harvested at each time point. C Gene Ontology (GO) term enrichment analysis of the RNA-seq experiment in (B). Genes that are differentially expressed in both MAPT Het and MAPT WT MAPT KD vs. MAPT WT NTC were analyzed with Enrichr, and top terms were plotted. Pathways related to axonogenesis and neuron morphology are colored magenta. D Heatmap summarizing ATAC-seq differential peaks at 4 weeks of differentiation. Two independent wells of neurons for each genotype/sgRNA combination were harvested. E Heatmap summarizing ATAC-seq transcription factor motif analysis at 4 weeks of differentiation from the same experiment in (D). Clusters were analyzed for pathway enrichment using Enrichr, and major pathways are annotated (“AP-1 Transcription Factor Network” and “Neuron Differentiation”). Quantification of cJun (F) and p-cJun (G) from the western blots in (S2D). Significance was calculated using one-way ANOVA with Šidák’s multiple comparison test, and comparisons were restricted within the donor background.CC BY · PubMed Central
Fig. 2 Proteomics uncovers altered phosphorylation of axonogenesis-related proteins in neurons with the MAPT V337M mutation. A Volcano plot showing changes in protein phosphorylation in MAPT Hom vs. MAPT WT neurons using mass spectrometry. Four independent 150 mm dishes of neurons for each condition were harvested after one week of differentiation. Dots represent individual phosphorylation sites. B Proteins with differential phosphorylation between MAPT Het, MAPT Hom neurons, and *MAPT Het vs. controls. Significance was calculated using multiple t-tests adjusted with Šidák single-step correction. Proteins with differential phosphorylation in all three datasets were filtered to identify 56 conserved proteins. C GO term enrichment of the 56 proteins from (B). Neuron morphology term bars are magenta, and splicing term bars are green. Top non-overlapping significant terms are shown. D Proteins with differential phosphorylation between MAPT Het vs. MAPT WT and two published mouse phosphoproteomics datasets, including tau KO mice and P301S mice vs. WT mice. Significance was calculated using multiple t-tests adjusted with Šidák single-step correction. Proteins with differential phosphorylation in all three datasets were filtered to identify 45 conserved proteins. E GO term enrichment of the 45 proteins from (D). Annotations are consistent with C. F String-DB protein-protein interaction network of proteins with differential phosphorylation in five datasets: MAPT Het, MAPT Hom, *MAPT Het vs isogenic controls, and tau KO mice and P301S mice vs. controls. The inner circle is colored based on the protein log2 fold change, and the outer circles are colored based on the log2 fold change for the indicated phosphorylation site. G Heatmap of phosphoproteomics data comparing MAPT KD vs. isogenic controls. Phosphosites that are decreased in MAPT Het vs. MAPT WT but that are rescued by tau knockdown in MAPT Het neurons are labeled in purple as a tau “gain-of-function” signature. Phosphosites that are changed in the same direction in MAPT WT MAPT KD, and MAPT Het vs. WT are labeled in orange as a tau “loss-of-function” signature.
Fig. 2 Proteomics uncovers altered phosphorylation of axonogenesis-related proteins in neurons with the MAPT V337M mutation. A Volcano plot showing changes in protein phosphorylation in MAPT Hom vs. MAPT WT neurons using mass spectrometry. Four independent 150 mm dishes of neurons for each condition were harvested after one week of differentiation. Dots represent individual phosphorylation sites. B Proteins with differential phosphorylation between MAPT Het, MAPT Hom neurons, and *MAPT Het vs. controls. Significance was calculated using multiple t-tests adjusted with Šidák single-step correction. Proteins with differential phosphorylation in all three datasets were filtered to identify 56 conserved proteins. C GO term enrichment of the 56 proteins from (B). Neuron morphology term bars are magenta, and splicing term bars are green. Top non-overlapping significant terms are shown. D Proteins with differential phosphorylation between MAPT Het vs. MAPT WT and two published mouse phosphoproteomics datasets, including tau KO mice and P301S mice vs. WT mice. Significance was calculated using multiple t-tests adjusted with Šidák single-step correction. Proteins with differential phosphorylation in all three datasets were filtered to identify 45 conserved proteins. E GO term enrichment of the 45 proteins from (D). Annotations are consistent with C. F String-DB protein-protein interaction network of proteins with differential phosphorylation in five datasets: MAPT Het, MAPT Hom, *MAPT Het vs isogenic controls, and tau KO mice and P301S mice vs. controls. The inner circle is colored based on the protein log2 fold change, and the outer circles are colored based on the log2 fold change for the indicated phosphorylation site. G Heatmap of phosphoproteomics data comparing MAPT KD vs. isogenic controls. Phosphosites that are decreased in MAPT Het vs. MAPT WT but that are rescued by tau knockdown in MAPT Het neurons are labeled in purple as a tau “gain-of-function” signature. Phosphosites that are changed in the same direction in MAPT WT MAPT KD, and MAPT Het vs. WT are labeled in orange as a tau “loss-of-function” signature.CC BY · PubMed Central
Fig. 3 MAPT V337M and MAPT knockdown disrupt axonogenesis. A (From left) Entire well of a 96 well plate stitched together and overlayed. The nucleus is marked with a magenta arrowhead, and the inset region of interest (ROI) is marked with a yellow box. The scale bars are 500 µm. NLS-mTagBFP (magenta) marks the nucleus (magenta arrowhead). Lck-mNeonGreen (green) labels the soma, axon and secondary neurites. Overlay showing the sparse labeled neuron with many unlabeled neurons close by. Example inset of a manually traced neuron showing the features measured. B Representative images of neurons expressing Lck-mNeonGreen (black). Nuclei are marked with magenta arrowheads, and the scale bars are 200 µm. Total neurite length (C), main axon length (D), axon branch length (E), and secondary neurite length (F) were quantified in day 5 neurons. Significance was calculated using one-way ANOVA with Šidák’s multiple comparison test.
Fig. 3 MAPT V337M and MAPT knockdown disrupt axonogenesis. A (From left) Entire well of a 96 well plate stitched together and overlayed. The nucleus is marked with a magenta arrowhead, and the inset region of interest (ROI) is marked with a yellow box. The scale bars are 500 µm. NLS-mTagBFP (magenta) marks the nucleus (magenta arrowhead). Lck-mNeonGreen (green) labels the soma, axon and secondary neurites. Overlay showing the sparse labeled neuron with many unlabeled neurons close by. Example inset of a manually traced neuron showing the features measured. B Representative images of neurons expressing Lck-mNeonGreen (black). Nuclei are marked with magenta arrowheads, and the scale bars are 200 µm. Total neurite length (C), main axon length (D), axon branch length (E), and secondary neurite length (F) were quantified in day 5 neurons. Significance was calculated using one-way ANOVA with Šidák’s multiple comparison test.CC BY · PubMed Central
Fig. 4 Tau phosphorylation is reduced in neurons with the MAPT V337M mutation. A Heatmap of tau phosphorylation from MAPT Hom or MAPT Het vs. MAPT WT. Phosphosites that were not detected in more than half of the replicates in both samples are marked in grey, and statistically significant phosphorylation changes are marked with an asterisk. B Protein domain map of 0N3R tau with detected phosphorylation sites labeled. Decreased phosphorylations detected in either MAPT Hom or MAPT Het neurons are labeled in blue. When phosphoproteomics could not distinguish between multiple potential phosphosites, all are included. C Western blot validating decreased tau phosphorylation in neurons with V337M tau after one week of differentiation. Two or three independent wells of neurons were harvested after one, two or three weeks of differentiation. AT8 was used to label tau pS202/pT205, and Tau13 was used to label total tau. D Quantification pS202/pT205 levels normalized to isogenic controls for MAPT Het and *MAPT Het from the western blots in (C). E WT, V337M and R406W tau were overexpressed via lentivirus in MAPT WT MAPT KD iPSCs. Three independent wells of neurons were harvested after one week of differentiation. pTau and total tau levels were analyzed by Western blot. F Quantification of the western blot in (E). Band intensities were normalized to actin and to the WT tau overexpression line. Significance was calculated using two-way ANOVA with Dunnet’s multiple comparisons test. G Kinase activity analysis from phosphorylation changes in neurons after one week of differentiation with the homozygous MAPT V337M mutation (MAPT Hom) vs. isogenic controls (MAPT WT). The log2 fold change of phosphopeptide abundance for annotated kinase substrates is plotted. The range is represented by the thin lines, the box represents the IQR, and the median is represented by a thick line. H Heatmap for kinase activity scores from all five phosphoproteomic datasets vs. isogenic controls.
Fig. 4 Tau phosphorylation is reduced in neurons with the MAPT V337M mutation. A Heatmap of tau phosphorylation from MAPT Hom or MAPT Het vs. MAPT WT. Phosphosites that were not detected in more than half of the replicates in both samples are marked in grey, and statistically significant phosphorylation changes are marked with an asterisk. B Protein domain map of 0N3R tau with detected phosphorylation sites labeled. Decreased phosphorylations detected in either MAPT Hom or MAPT Het neurons are labeled in blue. When phosphoproteomics could not distinguish between multiple potential phosphosites, all are included. C Western blot validating decreased tau phosphorylation in neurons with V337M tau after one week of differentiation. Two or three independent wells of neurons were harvested after one, two or three weeks of differentiation. AT8 was used to label tau pS202/pT205, and Tau13 was used to label total tau. D Quantification pS202/pT205 levels normalized to isogenic controls for MAPT Het and *MAPT Het from the western blots in (C). E WT, V337M and R406W tau were overexpressed via lentivirus in MAPT WT MAPT KD iPSCs. Three independent wells of neurons were harvested after one week of differentiation. pTau and total tau levels were analyzed by Western blot. F Quantification of the western blot in (E). Band intensities were normalized to actin and to the WT tau overexpression line. Significance was calculated using two-way ANOVA with Dunnet’s multiple comparisons test. G Kinase activity analysis from phosphorylation changes in neurons after one week of differentiation with the homozygous MAPT V337M mutation (MAPT Hom) vs. isogenic controls (MAPT WT). The log2 fold change of phosphopeptide abundance for annotated kinase substrates is plotted. The range is represented by the thin lines, the box represents the IQR, and the median is represented by a thick line. H Heatmap for kinase activity scores from all five phosphoproteomic datasets vs. isogenic controls.CC BY · PubMed Central
Fig. 5 CRISPR screens elucidate regulators of tau phosphorylation in neurons. A Pooled genetic screening workflow for tau pS202/pT205 levels in neurons. MAPT WT CRISPRi NGN2 iPSCs, MAPT Het CRISPRi NGN2 iPSCs, or MAPT WT CRISPRa NGN2 iPSCs were transduced by lentivirus with a pooled “druggable genome” sgRNA library targeting 2,318 genes enriched for kinases and phosphatases. iPSCs were differentiated into neurons. After two weeks, neurons were fixed, stained with AT8, and sorted for high or low AT8 staining. The high AT8 and low AT8 samples were sequenced to determine which sgRNAs were enriched in either fraction. B Scatter plot comparing CRISPRi screens in MAPT Het neurons vs. MAPT WT neurons. AT8 non-hits are labeled with grey circles, AT8 hits that also modify tau levels (using the T22 antibody as a surrogate for total tau levels) are labeled with “+”, and AT8-specific hits are labeled with black circles. Top genotype-specific hits are labeled in black, and key pathways are labeled in green (cytoskeleton), purple (Neuron projection development), and blue (p38 MAPK pathway). C Rank plot showing the results of the CRISPRa screen in MAPT WT neurons. AT8 non-hits are labeled in grey, and AT8 hits are labeled in black. Hits that are cytoskeleton-related genes are labeled in green, and hits that are related to neuron projection development are labeled in purple. D Detected tau phosphosites are mapped to the phenotype of known tau kinases from the CRISPRi/a screens. Tau phosphosites that were significantly different in either MAPT Hom or MAPT Het neurons vs. MAPT WT are indicated with blue text/boxes. Kinases whose knockdown or overexpression perturb tau phosphorylation at S202/T205 are indicated by red text/boxes. Overlap between significant kinases and differential phosphorylations is indicated by purple boxes. Grey boxes indicate phosphorylations by known tau kinases that are not significantly different or involved in tau pS202/T205. References for known tau kinase activity are indicated by the kinase name.
Fig. 5 CRISPR screens elucidate regulators of tau phosphorylation in neurons. A Pooled genetic screening workflow for tau pS202/pT205 levels in neurons. MAPT WT CRISPRi NGN2 iPSCs, MAPT Het CRISPRi NGN2 iPSCs, or MAPT WT CRISPRa NGN2 iPSCs were transduced by lentivirus with a pooled “druggable genome” sgRNA library targeting 2,318 genes enriched for kinases and phosphatases. iPSCs were differentiated into neurons. After two weeks, neurons were fixed, stained with AT8, and sorted for high or low AT8 staining. The high AT8 and low AT8 samples were sequenced to determine which sgRNAs were enriched in either fraction. B Scatter plot comparing CRISPRi screens in MAPT Het neurons vs. MAPT WT neurons. AT8 non-hits are labeled with grey circles, AT8 hits that also modify tau levels (using the T22 antibody as a surrogate for total tau levels) are labeled with “+”, and AT8-specific hits are labeled with black circles. Top genotype-specific hits are labeled in black, and key pathways are labeled in green (cytoskeleton), purple (Neuron projection development), and blue (p38 MAPK pathway). C Rank plot showing the results of the CRISPRa screen in MAPT WT neurons. AT8 non-hits are labeled in grey, and AT8 hits are labeled in black. Hits that are cytoskeleton-related genes are labeled in green, and hits that are related to neuron projection development are labeled in purple. D Detected tau phosphosites are mapped to the phenotype of known tau kinases from the CRISPRi/a screens. Tau phosphosites that were significantly different in either MAPT Hom or MAPT Het neurons vs. MAPT WT are indicated with blue text/boxes. Kinases whose knockdown or overexpression perturb tau phosphorylation at S202/T205 are indicated by red text/boxes. Overlap between significant kinases and differential phosphorylations is indicated by purple boxes. Grey boxes indicate phosphorylations by known tau kinases that are not significantly different or involved in tau pS202/T205. References for known tau kinase activity are indicated by the kinase name.CC BY · PubMed Central

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Research works printed but not linked: 2

  1. Alzheimer, A. Uber eigenartige Erkrankung der Hirnrinde. All Z. Psychiatr. 64, 146–148 (1907).
  2. Naseri, N. N. et al. Specific Combinations of Physiological Tau Phosphorylation Regulate Tau-Microtubule Interactions in Developing Neurons. bioRxiv, (2025).

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Metadata

Authors
Mohl, G. A., Dixon, G., Marzette, E., McKetney, J., Samelson, A. J., Serras, C. P., Jin, J., Ariqat, N., Keys, A., Chavira, C., Li, A., Boggess, S. C., Swaney, D. L., & Kampmann, M.
Affiliations
  • University of California, San Francisco (US)
  • Gladstone Institutes (US)
Corresponding author
Kampmann, Martin
ORCID
Venue
npj Dementia
Publisher
Springer Science and Business Media LLC
Published
2026-04-25
Volume
2
Issue
1
Pages
24-24
ISSN
3005-1940 (ISSN-L)
DOI
10.1038/s44400-026-00076-w
PMC
PMC13110130
OpenAlex
W7155651581
Semantic Scholar
b68a1dadd40ce1e2bfe2a5a84b9f13776ab141fb
Cited by
5
References
93
Citations by year
2026: 4
FWCI
5.73
Type
journal article
Language
en
Open access
Licence
Locations
  • npj Dementia (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (submittedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
Funders
  • A.P. Gianni Foundation (Postdoctoral Fellowship)
  • National Institute for neurological disorders and stroke (U54 NS123746, U54 NS100717)
  • National Institute on Aging (F32 AG063487, R01 AG062359)
  • Alzheimer’s Association (23AARF-1027616)
  • Rainwater Charitable Foundation (Tau Consortium Award)
  • Chan Zuckerberg Initiative (Ben Barres Early Career Acceleration Award)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
tau phosphorylation, axonogenesis, axon morphology, iPSC-derived neurons, p38 MAPK pathway, tau aggregation, Alzheimer's disease, frontotemporal dementia, neuronal development

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