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Tau physiology and pathomechanisms in frontotemporal lobar degeneration

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Bodea, Liviu‐Gabriel, Eckert, Anne, Ittner, Lars Matthias, Piguet, Olivier, Götz, Jürgen·2016·Journal of Neurochemistry
DOI 10.1111/jnc.13600PMC PMC5094566
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Abstract

Frontotemporal lobar degeneration ( FTLD ) has been associated with toxic intracellular aggregates of hyperphosphorylated tau ( FTLD ‐tau). Moreover, genetic studies identified mutations in the MAPT gene encoding tau in familial cases of the disease. In this review, we cover a range of aspects of tau function, both in the healthy and diseased brain, discussing several in vitro and in vivo models. Tau structure and function in the healthy brain is presented, accentuating its distinct compartmentalization in neurons and its role in microtubule stabilization and axonal transport. Furthermore, tau‐driven pathology is discussed, introducing current concepts and the underlying experimental evidence. Different aspects of pathological tau phosphorylation, the protein's genomic and domain organization as well as its spreading in disease, together with MAPT ‐associated mutations and their respective models are presented. Dysfunction related to other post‐transcriptional modifications and their effect on normal neuronal functions such as cell cycle, epigenetics and synapse dynamics are also discussed, providing a mechanistic explanation for the observations made in FTLD ‐tau cases, with the possibility for therapeutic intervention. image In this review, we cover aspects of tau function, both in the healthy and diseased brain, referring to different in vitro and in vivo models. In healthy neurons, tau is compartmentalized, with higher concentrations found in the distal part of the axon. Cargo molecules are sensitive to this gradient. A disturbed tau distribution, as found in frontotemporal lobar degeneration ( FTLD ‐tau), has severe consequences for cellular physiology: tau accumulates in the neuronal soma and dendrites, leading among others to microtubule depolymerization and impaired axonal transport. Tau forms insoluble aggregates that sequester additional molecules stalling cellular physiology. Neuronal communication is gradually lost as toxic tau accumulates in dendritic spines with subsequent degeneration of synapses and synaptic loss. Thus, by providing a mechanistic explanation for the observations made in FTLD ‐tau cases, arises a possibility for therapeutic interventions. This article is part of the Frontotemporal Dementia special issue .

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  • These tau changes correlate with degeneration of synapses and neuronal loss in frontal and temporal cortices.

    “These changes correlate with degeneration of synapses and neuronal loss in frontal and temporal cortices (Bodea et al., 2016; Clare et al., 2010).”

    From ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids (2021) · cites this paper as Bodea et al., 2016

    The section ‘Role of tau in dendritic spines and synaptic impairment’ links pathological tau to synaptic degeneration and reports neuronal loss in a tau mouse model. The paper also describes frontal and temporal cortical atrophy in FTLD, but it does not establish that the tau changes correlate with both synaptic degeneration and neuronal loss specifically in those cortices. The mouse-model comparison distinguishes tau changes associated with synaptic loss from those associated with neuronal loss. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Pathologic studies reveal accumulation of filamentous, hyperphosphorylated tau protein in cerebral cortical and hippocampal neurons and glia, and tau redistribution from axons to the somatodendritic compartment.

    “Pathologic studies reveal accumulation of filamentous, hyperphosphorylated tau protein (P-tau) in cerebral cortical and hippocampal neurons and glia, and tau redistribution from axons to the somatodendritic compartment.”

    From ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids (2021) · cites this paper as Bodea et al., 2016

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Authors
Bodea, L., Eckert, A., Ittner, L. M., Piguet, O., & Götz, J.
Affiliations
  • The University of Queensland (AU)
  • University of Basel (CH)
  • UNSW Sydney (AU)
  • Neuroscience Research Australia (AU)
Corresponding author
Götz, Jürgen
ORCID
Venue
Journal of Neurochemistry
Publisher
Wiley
Published
2016-06-15
Volume
138
Issue
S1
Pages
71-94
ISSN
  • 0022-3042 (ISSN-L)
  • 1471-4159
DOI
10.1111/jnc.13600
PMC
PMC5094566
OpenAlex
W2431821511
Cited by
104
References
35
Citations by year
2026: 5 · 2025: 6 · 2024: 16 · 2023: 7 · 2022: 7 · 2021: 19 · 2020: 7 · 2019: 13 · 2018: 12 · 2017: 9 · 2016: 3
FWCI
1.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neurochemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Australian Research Council (DP1330010193 2)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
tau protein, frontotemporal lobar degeneration, hyperphosphorylated tau, MAPT mutations, tau phosphorylation, axonal transport, microtubule stabilization, tau aggregates, synaptic loss, post-transcriptional modification, epigenetics, cell cycle, tau propagation, disease models, therapeutic interventions
MeSH terms
Animals, Humans, tau Proteins, Tauopathies, Frontotemporal Lobar Degeneration

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