Tau Phosphorylation and Aggregation in the Developing Human Brain

Hefti, Marco M.; Kim, SoongHo; Bell, Aaron; Betters, Ryan K; Fiock, Kimberly L.; Iida, Megan A.; Smalley, Martin E.; Farrell, Kurt; Fowkes, Mary; Crary, John F.

doi:10.1093/jnen/nlz073

Cited by 46 publications

(42 citation statements)

References 43 publications

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“…Nevertheless, these findings are consistent with previous work that suggest that the developing brain is more resilient to formation of toxic aggregates. 54 Similar to our data, in 6 patients who died within 3 days following severe TBI, the only TDP-43 pathology observed was an increase of pTDP-43 (S409/410) fragments in the nuclear fraction of the frontal cortex. 55 Interestingly, this study also showed a TBI-mediated exacerbation of TDP-43 pathology and cell death in a transgenic mouse expressing mutant TDP-43 (A315T), however, significant differences in TDP-43 pathologies between mouse and human samples were observed, thus necessitating the study of TBI in human cells.…”

Section: Discussionsupporting

confidence: 91%

A model of traumatic brain injury using human iPSC-derived cortical brain organoids

Lai

Berlind

Fricklas

et al. 2020

Preprint

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AbstractTraumatic brain injury confers a significant and growing public health burden and represents a major environmental risk factor for dementia. Previous efforts to model traumatic brain injury and elucidate pathologic mechanisms have been hindered by complex interactions between multiple cell types, biophysical, and degenerative properties of the human brain. Here, we use high-intensity focused ultrasound to induce mechanical injury in 3D human pluripotent stem cell-derived cortical organoids to mimic traumatic brain injury in vitro. Our results show that mechanically injured organoids recapitulate key hallmarks of traumatic brain injury, phosphorylation of tau and TDP-43, neurodegeneration, and transcriptional programs indicative of energy deficits. We present high-intensity focused ultrasound as a novel, reproducible model of traumatic brain injury in cortical organoids with potential for scalable and temporally-defined mechanistic studies.

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Section: Discussionsupporting

confidence: 91%

A model of traumatic brain injury using human iPSC-derived cortical brain organoids

Lai

Berlind

Fricklas

et al. 2020

Preprint

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“…This may explain the presence of higher than expected levels of tau protein in immature regions by Western blotting compared with IHC. We did not attempt to quantify individual tau isoforms since it has been previously demonstrated on both the RNA and protein level that fetal tau consists exclusively of the shortest (0N3R) isoform, and the extensive phosphorylation of human fetal tau makes identifying individual isoforms on Western blotting difficult without phosphatase pretreatment (Hefti et al, 2018(Hefti et al, , 2019.…”

Section: Discussionmentioning

confidence: 99%

“…Tau also appears to play a role in glutamatergic signaling (Miller et al, 2014;Tracy and Gan, 2017), excitotoxicity (Liang et al, 2009), and epileptogenesis (Liu et al, 2017). Recently, it was demonstrated that human fetal tau has a predominantly short-isoform, hyperphosphorylated phenotype similar to that seen in AD (Hefti et al, 2018(Hefti et al, , 2019. It remains unclear, however, what cell types express tau in the developing human brain and when in development this occurs.…”

Section: Introductionmentioning

confidence: 99%

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

Fiock

Smalley

Crary

et al. 2020

eNeuro

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Although best known for its role in Alzheimer's disease (AD), tau is expressed throughout brain development, although it remains unclear when and which cell types this expression occurs and how it affects disease states in both fetal and neonatal periods. We thus sought to map tau mRNA and protein expression in the developing human brain at the cellular level using a combination of existing single-cell RNA sequencing (sc-RNAseq) data, RNA in situ hybridization (RNAscope), and immunohistochemistry (IHC). Using sc-RNAseq, we found that tau mRNA expression begins in radial glia but increases dramatically as migrating neuronal precursors mature. Specifically, TBR1 1 maturing neurons and SYN 1 mature neurons showed significantly higher mRNA expression than GFAP 1 /NES 1 radial glia or TBR2 1 intermediate progenitors. By RNAscope, we found Significance Statement Tau is a mediator of neurotoxicity across multiple neurodegenerative diseases, including Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). With the recent failure of b-amyloid-targeted therapies in AD to improve cognitive function, there is increasing interest in tau targeted therapies. Tau is expressed throughout brain development, but the function and normal developmental expression remains unclear. Here, we demonstrate that tau expression begins early during neuronal maturation in both human fetal brain and induced pluripotent stem cell (iPSC)-derived cortical organoids. This work forms the basis for future research into the developmental regulation of tau expression, which may provide future tau-related therapeutic targets.

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“…Currently, the levels of A40/A42 peptides in patient CSF and blood are implicated as disease biomarkers in the clinic 7,9 . Tau protein is a key component of microtubule assembly in axons and its function is regulated by phosphorylation on multiple residues including threonine 181 (Tau-pT181) 10 . Similar to A peptides, Tau protein and its pT181 form are also detectable in CSF and blood specimens; their levels are associated with disease progression 11 .…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Sleep Treatment Improves Neuropsychological Symptoms and Reduces Blood Aβ42/pTau Protein in Alzheimer's Disease Patients: a Longitudinal Study

Li¹,

Huang²,

Li³

et al. 2021

Preprint

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Background: Amyloid β peptide-42 (Aβ42) and phosphorylated Tau on Threonine 181 (Tau-pT181) are the core biomarkers in Alzheimer’s disease. Accumulated evidence showed an aberrant elevation of these biomarkers due to sleep disturbance. However, it is not clear if improving sleep quality reduces Aβ42 and Tau-pT181 in Alzheimer’s disease patients.Methods: A longitudinal study was conducted on 126 patients with mild-moderate dementia due to Alzheimer’s disease. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Behavioral and neuropsychological assessment was conducted using multiple self-reporting questionnaire score systems. Aβ42 and Tau-pT181 levels in blood specimens were measured using an ELISA assay kit. All patients received Donepezil treatment for Alzheimer’s disease. Sleep disorders were individually managed with either medication or physical therapy according to their symptom categories.Results: Of the 126 cases, 93 (73.8%) patients were diagnosed with sleep disorders. The PSQI scores significantly correlated with depression and anxiety scores, as well as Aβ42 and Tau-pT181 levels. Also, a significant correlation was found among depression, anxiety, Aβ42 and Tau-pT181 in all patients. Sleep intervention drastically reduced PSQI score, as well as Aβ42 and Tau-pT181 levels, in parallel with improved cognition, deterioration and anxiety scores. Dementia and depression scores were improved only in patients who completely recovered (PSQI < 7) after sleep treatment. There was a 35.9% reduction of Aβ42 levels and a 32.8% reduction of Tau-pT181 levels in this subgroup of patients (56 cases). Conversely, the reduction extent was only 6.9% for Aβ42 and 12.2% for Tau-pT181 in patients who did not completely recover (PSQI ≥ 7 post treatment, 37 cases). Multiple logistic regression analysis revealed that Aβ42 level is the strongest risk factor for sleep disorder incidence and incomplete recovery after sleep treatment.Conclusion: Sleep quality score is associated with patient depression and anxiety status, as well as blood Aβ42 and Tau-pT181 levels. A complete recovery is critical for a full improvement of all behavioral and neuropsychological assessments, which is also associated with a deep reduction of Aβ42 and Tau-pT181 levels. Aβ42 level is a prognostic factor for a diagnosis of sleep disorder and treatment responsiveness.

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Tau Phosphorylation and Aggregation in the Developing Human Brain

Cited by 46 publications

References 43 publications

A model of traumatic brain injury using human iPSC-derived cortical brain organoids

A model of traumatic brain injury using human iPSC-derived cortical brain organoids

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

WITHDRAWN: Sleep Treatment Improves Neuropsychological Symptoms and Reduces Blood Aβ42/pTau Protein in Alzheimer's Disease Patients: a Longitudinal Study

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