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.

Tau Oligomers Associate with Inflammation in the Brain and Retina of Tauopathy Mice and in Neurodegenerative Diseases

“…Inspection of the retina has been suggested as a potential biomarker for the diagnosis of neurodegeneration [24–26]. There is a higher incidence of age-related macular degeneration in patients with AD [27].…”

“…Tau oligomers were recently found in the retina of a rat model for glaucoma and suppression of tau reduced the occurrence of retinal degeneration [28]. Also, there is evidence of large protein deposits, such as Aβ and tau, being present in the retina of AD patients and in tauopathy mice as well as the presence of inflammation [24–26, 29, 30]. Early detection of AD, possibly even prodromal detection, would allow for the early intervention and prevention of neurodegeneration prior to major synapse loss and cognitive decline.…”

“…The tauopathy mice that we used contained the P301L mutation, which is implicated in some genetic tauopathies. In addition, this mutation, along with the related P301S mutation, has been associated with increased inflammation in the brain as well as retinal deficits [24, 33]. However, these events were investigated in isolation and were not investigated thoroughly to determine if they are linked.…”

Neuroinflammatory challenges compromise neuronal function in the aging brain: Postoperative cognitive delirium and Alzheimer’s disease

“…Several studies have shown that BDNF expression levels can decrease in models of POD and AD, with IL-1β [40,135,166,136], Aβ [226–229], and tau [230] directly affecting BDNF-associated intracellular signaling pathways and synaptic plasticity. Clinical studies in patients with the BDNF Val66Met polymorphism find that cognitive impairments associated with changes in BDNF occur more in preclinical stages of AD and not in advanced stages of AD (defined by high Aβ deposits) [231–233].…”

Advanced imaging of tau pathology in Alzheimer Disease: New perspectives from super resolution microscopy and label‐free nanoscopy

“…Further, recombinant Tau fibrils induce aggregation of intracellular full‐length Tau in cultured cells (Kfoury et al, ). In vivo, injection of brain extracts from the P301S Tau transgenic model of tauopathy or from human AD brain into the brains of mice expressing wild type human Tau induces assembly of wild type Tau into filaments and spreading of Tau pathology across the brain (Clavaguera et al, ; Mazzaro et al, ). Similar results were obtained with injection of filaments of recombinant human Tau, which cause rapid induction of Tau inclusions in the site of injection and subsequent propagation of Tau pathology to interconnected areas (Iba et al, ).…”