Increased Tau Expression Correlates with Neuronal Maturation in the Developing Human Cerebral Cortex

Fiock, Kimberly L.; Smalley, Martin E.; Crary, John F.; Pașca, Anca M.; Hefti, Marco M.

doi:10.1523/eneuro.0058-20.2020

Cited by 27 publications

(26 citation statements)

References 31 publications

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“…Gene expression profiling of different parts of human fetal cortex tissues revealed higher expression of TGF-β1 and TGF-β RI, RII, and RIII during the fourth post-conception week (pcw) compared to pcw 16-19, showing a progressive decrease of gene expression (Figures 1Aiiv). This expression pattern is similar to specific NSC transcripts, such as nestin (NES), pax-6 and hes-1 (Figures 1Bi-iii) and it is reciprocal to the gene expression of doublecortin (DCX) (Figure 1Biv), a gene expressed by neuronal progenitor cells, and neuron-related genes, such as axonal protein Tau (MAPT) (Fiock et al, 2020) and CamKinase (CamK2b) (Wayman et al, 2008;Figures 1Ci,ii), as well as astrocytes-related genes, such as GFAP and S100beta (Figures 1Ciii,iv). In contrast, TGF-β2 and β3 are expressed at lower levels during the earlier stages of human fetal cortex development (before pcw 10-13) compared to pcw 19-24, with a gradual up-regulation starting after pcw 10-13 reaching their maximum expression at late fetal stages (24 till 38 pcw) (Figures 1Di,ii) which is comparable to the genes involved in synaptogenesis, such as post-synaptic density protein [PSD-93 aka DLG2 (disc large homolog2)] and BDNF (Figures 1Diii,iv).…”

Section: Tgf-β Is a Potential Physiological Regulator Of Neural Stem Cell Proliferation Neuronal And Glial Differentiation During Early Hmentioning

confidence: 69%

TGF-β1 Suppresses Proliferation and Induces Differentiation in Human iPSC Neural in vitro Models

Izsák

Vizlin‐Hodzic

Iljin

et al. 2020

Front. Cell Dev. Biol.

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Persistent neural stem cell (NSC) proliferation is, among others, a hallmark of immaturity in human induced pluripotent stem cell (hiPSC)-based neural models. TGF-β1 is known to regulate NSCs in vivo during embryonic development in rodents. Here we examined the role of TGF-β1 as a potential candidate to promote in vitro differentiation of hiPSCs-derived NSCs and maturation of neuronal progenies. We present that TGF-β1 is specifically present in early phases of human fetal brain development. We applied confocal imaging and electrophysiological assessment in hiPSC-NSC and 3D neural in vitro models and demonstrate that TGF-β1 is a signaling protein, which specifically suppresses proliferation, enhances neuronal and glial differentiation, without effecting neuronal maturation. Moreover, we demonstrate that TGF-β1 is equally efficient in enhancing neuronal differentiation of human NSCs as an artificial synthetic small molecule. The presented approach provides a proof-of-concept to replace artificial small molecules with more physiological signaling factors, which paves the way to improve the physiological relevance of human neural developmental in vitro models.

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Section: Tgf-β Is a Potential Physiological Regulator Of Neural Stem Cell Proliferation Neuronal And Glial Differentiation During Early Hmentioning

confidence: 69%

TGF-β1 Suppresses Proliferation and Induces Differentiation in Human iPSC Neural in vitro Models

Izsák

Vizlin‐Hodzic

Iljin

et al. 2020

Front. Cell Dev. Biol.

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“…MAPT mutation tau V337M that shows a progressive accumulation of pathogenic tau, including cleaved tau, p-tau, and oligomeric tau, and (c) the neuroprotective effect of caspase pharmacological intervention. Different from most studies, we maintained tau V337M and tau WT iNs for up to three months to avoid capturing artefactual effects caused by physiological overexpression of p-tau forms in the developing neurons (41,47).…”

Section: Discussionmentioning

confidence: 99%

Caspase inhibition mitigates tau cleavage and neurotoxicity in iPSC-induced neurons with the V337MMAPTmutation

Theofilas

Wang

Butler

et al. 2021

Preprint

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Tau post-translational modifications (PTMs) are associated with progressive tau accumulation and neuronal loss in tauopathies, including forms of frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD). Proteolytic cleavage of tau by active caspases, including caspase-6, represents an underexplored tau PTM implicated in tau pathology. Caspase-cleaved tau is toxic and prone to self-aggregation in experimental models. To elucidate the presence and temporal course of caspase activation, tau cleavage, and neuronal death, we generated two neoepitope monoclonal antibodies (mAbs) against caspase-6 tau proteolytic sites and cortical neurons from induced pluripotent stem cells (iPSCs) with the frontotemporal dementia (FTD)-causing V337M MAPT mutation. FTLD V337M MAPT and AD postmortem brains showed positivity for both cleaved tau mAbs as well as active caspase-6. Relative to isogenic wild-type MAPT controls, V337M MAPT neurons showed a time-dependent increase in pathogenic tau in the form of tau oligomers, caspase-cleaved tau, and p-tau. Accumulation of toxic tau species in 3-month V337M MAPT neurons also increased vulnerability to stress, which was pharmacologically rescued by caspase inhibition. We propose a model in which time-dependent accumulation of caspase-cleaved tau in V337M MAPT neurons promotes neurotoxicity that is reversed by caspase-6 inhibition. Caspase-cleaved tau may be a biomarker of tauopathy, and caspases could be viable targets for therapeutic intervention against tau pathogenesis in FTLD and other tauopathies.SignificanceThe mechanisms leading to tau pathology in frontotemporal dementia (FTD) and Alzheimer’s disease (AD) remain elusive. Experimental studies in AD demonstrate that tau cleavage by active caspase-6 contributes to tau pathology since cleaved tau may be toxic and prone to self-aggregation. Yet, the role of caspase-cleaved tau in promoting toxicity and cell death is unclear. Here, we generated two neoepitope monoclonal antibodies against caspase-6 tau and evaluated tau cleavage in postmortem human brains, iPSC-induced cortical neurons with the FTD-causing V337M MAPT mutation, and isogenic wild-type MAPT controls. Our results demonstrate a time-dependent accumulation of caspase-cleaved tau and increased neurotoxicity in the mutant iNs that is reversed by caspase-6 inhibition. Caspases could be viable therapeutic targets against tau pathology in tauopathies.

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“…Choi et al used neurons derived from immortalised neural precursor cells, and after 7 weeks differentiation observed increased 4R tau transcripts in 3D compared with the same cells cultured in 2D (20). A second study used iPSC-neurons coated on alginate beads, and detected transcripts from all tau isoforms after 25 weeks of differentiation, although 0N3R was still the predominant tau species (75%+ of total tau) (21).Another recent study compared tau expression in cerebral organoids with fetal brain, although they only assessed the location of tau transcripts using RNA scope and no assessment of tau splicing was undertaken (40). The MAPT 10+16 mutation had a dramatic effect on tau splicing after 300 DIV, resulting in a near-complete conversion to 4R tau when present in a biallelic form.…”

Section: Discussionmentioning

confidence: 99%

Engineered Cerebral Organoids Recapitulate Adult Tau Expression and Disease-relevant Changes in Tau Splicing

Lovejoy

Alatza

Arber

et al. 2020

Preprint

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The tauopathies are a collection of clinically and pathologically diverse neurodegenerative disorders characterised by tau pathology. The tau protein exists as multiple protein isoforms in the adult human CNS, generated by alternative splicing of the MAPT gene. Disruptions to tau splicing are associated with a number of tauopathies, however, in vitro and in vivo models to understand the consequences of disrupted tau splicing have been lacking, due in part to species differences in tau splicing and the developmental regulation of tau in human neurons. We investigated the utility of iPSC-derived cerebral organoids to model key aspects of tau biology. Cerebral organoids showed high variability in neuronal content and tau expression. To reduce this heterogeneity, we generated engineered cerebral organoids (enCORs), which use a floating scaffold to increase the efficiency of neural induction and reduce heterogeneity. We show that enCORs provide a robust and reproducible in vitro system for the analysis of tau expression and splicing in a 3D model. To investigate the effect of tau mutations, we generated enCORs from an isogenic series of iPSC with the MAPT 10+16 and P301S mutations. The presence of tau splicing mutations results in disease-associated alterations in tau expression, specifically a dose-dependent increase in 4R tau isoforms in the presence of the MAPT 10+16 variant. While the developmental regulation of tau splicing is conserved, maturation of tau splicing is accelerated in 3D cultures compared to 2D cultures. Finally, enCORs with coding mutations in MAPT are able to produce seed-competent tau species, suggesting enCORs recapitulate early features of tau pathology. In summary, enCORs provide a novel, robust in vitro system for the study of tau in development and disease.

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Increased Tau Expression Correlates with Neuronal Maturation in the Developing Human Cerebral Cortex

Cited by 27 publications

References 31 publications

TGF-β1 Suppresses Proliferation and Induces Differentiation in Human iPSC Neural in vitro Models

TGF-β1 Suppresses Proliferation and Induces Differentiation in Human iPSC Neural in vitro Models

Caspase inhibition mitigates tau cleavage and neurotoxicity in iPSC-induced neurons with the V337MMAPTmutation

Engineered Cerebral Organoids Recapitulate Adult Tau Expression and Disease-relevant Changes in Tau Splicing

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