Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy

Forrest, Shelley L.; Lee, Seojin; Nassir, Nasna; Martínez-Valbuena, Iván; Sackmann, Valerie; Li, Jun; Ahmed, Awab; Tartaglia, Carmela; Ittner, Lars M.; Lang, Anthony E.; Uddin, Mohammed; Kovács, Gábor G.

doi:10.1007/s00401-023-02604-x

Cited by 13 publications

(15 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such APP-FPN stabilization is demonstrated to be mediated by tau transport of APP to the cell membrane [42]. As tau expression is significantly higher in neurons [47], we may speculate that glia may have other mechanisms for maintaining iron homeostasis, which do not involve APP, making them relatively less vulnerable to Aβ-pathology-induced iron dysregulation. On the other hand, evidence suggests that astrocytes respond to extracellular Aβ pathology.…”

Section: Hypothesis 1 231 Iron Accumulation Is a Consequence Of Patho...mentioning

confidence: 95%

The Irony of Iron: The Element with Diverse Influence on Neurodegenerative Diseases

Lee,

Kovacs

2024

IJMS

Self Cite

View full text Add to dashboard Cite

Iron accumulation in the brain is a common feature of many neurodegenerative diseases. Its involvement spans across the main proteinopathies involving tau, amyloid-beta, alpha-synuclein, and TDP-43. Accumulating evidence supports the contribution of iron in disease pathologies, but the delineation of its pathogenic role is yet challenged by the complex involvement of iron in multiple neurotoxicity mechanisms and evidence supporting a reciprocal influence between accumulation of iron and protein pathology. Here, we review the major proteinopathy-specific observations supporting four distinct hypotheses: (1) iron deposition is a consequence of protein pathology; (2) iron promotes protein pathology; (3) iron protects from or hinders protein pathology; and (4) deposition of iron and protein pathology contribute parallelly to pathogenesis. Iron is an essential element for physiological brain function, requiring a fine balance of its levels. Understanding of disease-related iron accumulation at a more intricate and systemic level is critical for advancements in iron chelation therapies.

show abstract

Section: Hypothesis 1 231 Iron Accumulation Is a Consequence Of Patho...mentioning

confidence: 95%

The Irony of Iron: The Element with Diverse Influence on Neurodegenerative Diseases

Lee,

Kovacs

2024

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Origins Of α-Syn and Tau In Astrocytesmentioning

confidence: 99%

“…Recently, by using RNAscope imaging and single-nuclear RNAseq, Forrest and colleagues have shown the presence of the MAPT transcript in astrocytes (other than neurons and oligodendrocytes) both in patients affected by PSP and in control subjects [ 79 ]. Interestingly, the amount of MAPT in PSP patients was similar between healthy and tufted astrocytes [ 79 ]. Moreover, by using the same techniques, Fiock and colleagues found that the number of astrocytes expressing MAPT and the amount of MAPT expressed by each astrocyte is comparable between patients affected by AD, CBD, PSP and healthy controls [ 80 ].…”

Section: Origins Of α-Syn and Tau In Astrocytesmentioning

confidence: 99%

“…As proposed in the first paper, it is likely that astrocytes express a basal amount of Tau, whose accumulation exacerbates upon the uptake of neuron-released Tau. Alternatively, some still undefined conditions may trigger the autonomous aggregation of Tau within astrocytes [ 79 ]. This latter observation could explain why in some pathological conditions, such as PSP, CBD and Pick’s disease, astrocytes show deposits of Tau in the absence of neuronal Tau [ 81 ].…”

Section: Origins Of α-Syn and Tau In Astrocytesmentioning

confidence: 99%

See 1 more Smart Citation

Brain clearance of protein aggregates: a close-up on astrocytes

Giusti,

Kaur,

Giusto

et al. 2024

Mol Neurodegeneration

View full text Add to dashboard Cite

Protein misfolding and accumulation defines a prevailing feature of many neurodegenerative disorders, finally resulting in the formation of toxic intra- and extracellular aggregates. Intracellular aggregates can enter the extracellular space and be subsequently transferred among different cell types, thus spreading between connected brain districts.Although microglia perform a predominant role in the removal of extracellular aggregated proteins, mounting evidence suggests that astrocytes actively contribute to the clearing process. However, the molecular mechanisms used by astrocytes to remove misfolded proteins are still largely unknown.Here we first provide a brief overview of the progressive transition from soluble monomers to insoluble fibrils that characterizes amyloid proteins, referring to α-Synuclein and Tau as archetypical examples. We then highlight the mechanisms at the basis of astrocyte-mediated clearance with a focus on their potential ability to recognize, collect, internalize and digest extracellular protein aggregates. Finally, we explore the potential of targeting astrocyte-mediated clearance as a future therapeutic approach for the treatment of neurodegenerative disorders characterized by protein misfolding and accumulation.

show abstract

“…In rodent models, astrocytic tau cannot propagate in the absence of neuronal tau expression [ 26 ], and human single-cell sequencing and RNA in situ hybridization data do not show an upregulation of tau expression in astrocytes from PSP patients [ 13 , 27 ]. Astrocytes will also readily take up recombinant tau fibrils or monomers in vitro [ 14 , 17 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

Determinants of astrocytic pathology in stem cell models of primary tauopathies

Fiock,

Hook,

Hefti

2023

acta neuropathol commun

View full text Add to dashboard Cite

Astrocytic tau aggregates are seen in several primary and secondary tauopathies, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and chronic traumatic encephalopathy (CTE). In all of these diseases, astrocytic tau consists mostly of the longer (4R) tau isoform, even when adjacent neuronal aggregates consist of a mixture of 3- and 4R tau, as in CTE. Even the rare astrocytic tau aggregates seen in Pick’s disease appear to contain both 3R and 4R tau. The reasons for this, and the mechanisms by which astrocytic tau aggregates form, remain unclear. We used a combination of RNA in situ hybridization and immunofluorescence in post-mortem human brain tissue, as well as tau uptake studies in human stem cell-derived astrocytes, to determine the origins of astrocytic tau in 4R tauopathies. We found no differences in tau mRNA expression between diseases or between tau positive and negative astrocytes within PSP. We then found that stem cell-derived astrocytes preferentially take up long isoform (4R) recombinant tau and that this uptake is impaired by induction of reactivity with inflammatory stimuli or nutritional stress. Astrocytes exposed to either 3R or 4R tau also showed downregulation of genes related to astrocyte differentiation. Our findings suggest that astrocytes preferentially take up neuronal 4R tau from the extracellular space, potentially explaining why 4R tau is the predominant isoform in astrocytic tau aggregates.

show abstract

Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy

Cited by 13 publications

References 73 publications

The Irony of Iron: The Element with Diverse Influence on Neurodegenerative Diseases

The Irony of Iron: The Element with Diverse Influence on Neurodegenerative Diseases

Brain clearance of protein aggregates: a close-up on astrocytes

Determinants of astrocytic pathology in stem cell models of primary tauopathies

Contact Info

Product

Resources

About