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Tau-Driven Neuronal and Neurotrophic Dysfunction in a Mouse Model of Early Tauopathy
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2016 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 36, no 7, 2086-2100 p.Article in journal (Refereed) Published
Abstract [en]

Tauopathies are neurodegenerative diseases characterized by intraneuronal inclusions of hyperphosphorylated tau protein and abnormal expression of brain-derived neurotrophic factor (BDNF), a key modulator of neuronal survival and function. The severity of both these pathological hallmarks correlate with the degree of cognitive impairment in patients. However, how tau pathology specifically modifies BDNF signaling and affects neuronal function during early prodromal stages of tauopathy remains unclear. Here, we report that the mild tauopathy developing in retinal ganglion cells (RGCs) of the P301S tau transgenic (P301S) mouse induces functional retinal changes by disrupting BDNF signaling via the TrkB receptor. In adult P301S mice, the physiological visual response of RGCs to pattern light stimuli and retinal acuity decline significantly. As a consequence, the activity-dependent secretion of BDNF in the vitreous is impaired in P301S mice. Further, in P301S retinas, TrkB receptors are selectively upregulated, but uncoupled from downstream extracellular signal-regulated kinase (ERK) 1/2 signaling. We also show that the impairment of TrkB signaling is triggered by tau pathology and mediates the tau-induced dysfunction of visual response. Overall our results identify a neurotrophin-mediated mechanism by which tau induces neuronal dysfunction during prodromal stages of tauopathy and define tau-driven pathophysiological changes of potential value to support early diagnosis and informed therapeutic decisions.

Place, publisher, year, edition, pages
2016. Vol. 36, no 7, 2086-2100 p.
Keyword [en]
BDNF, electroretinography, neuronal dysfunction, retinal ganglion cells, tau protein, TrkB receptor
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-129999DOI: 10.1523/JNEUROSCI.0774-15.2016ISI: 000370818700003PubMedID: 26888921OAI: oai:DiVA.org:umu-129999DiVA: diva2:1064941
Available from: 2017-01-13 Created: 2017-01-11 Last updated: 2017-01-13Bibliographically approved

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CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf