title: Tau-Driven Neuronal and Neurotrophic Dysfunction in a Mouse Model of Early Tauopathy.
abstract: 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.
  
  
  CONCLUSIONS
  This work highlights the potential molecular mechanisms by which initial tauopathy induces neuronal dysfunction. Combining clinically used electrophysiological techniques (i.e., electroretinography) and molecular analyses, this work shows that in a relevant model of early tauopathy, the retina of the P301S mutant human tau transgenic mouse, mild tau pathology results in functional changes of neuronal activity, likely due to selective impairment of brain-derived neurotrophic factor signaling via its receptor, TrkB. These findings may have important translational implications for early diagnosis in a subset of Alzheimer's disease patients with early visual symptoms and emphasize the need to clarify the pathophysiological changes associated with distinct tauopathy stages to support informed therapeutic decisions and guide drug discovery.
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Mazzaro
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Barini
authors.affiliation: Cambridge Centre for Brain Repair, University of Cambridge, Cambridge CB2 2PY, United Kingdom, and.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Spillantini
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
authors.forename: Michel
authors.initials: M
authors.lastname: Goedert
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Medini
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy, laura.gasparini@abbvie.com.
authors.forename: Laura
authors.identifier: http://orcid.org/0000-0003-3894-9898
authors.initials: L
authors.lastname: Gasparini
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D004596:Electroretinography; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000235:genetics; D010775:Photic Stimulation; D020813:Receptor, trkB / Q000235:genetics; D012165:Retinal Ganglion Cells; D024801:Tauopathies / Q000503:physiopathology*; D014020:Tissue Extracts / Q000494:pharmacology; D014785:Vision, Ocular; D014792:Visual Acuity; D016875:tau Proteins
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D014020:Tissue Extracts; D016875:tau Proteins; D020813:Receptor, trkB
keywords: BDNF; TrkB receptor; electroretinography; neuronal dysfunction; retinal ganglion cells; tau protein