Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis

Abstract

Tau is a microtubule‐associated neuronal protein found mainly in axons. However, its presence in dendrites and dendritic spines is particularly relevant due to its involvement in synaptic plasticity and neurodegeneration. Here, we show that Tau plays a novel in vivo role in the morphological and synaptic maturation of newborn hippocampal granule neurons under basal conditions. Furthermore, we reveal that Tau is involved in the selective cell death of immature granule neurons caused by acute stress. Also, Tau deficiency protects newborn neurons from the stress‐induced dendritic atrophy and loss of postsynaptic densities (PSDs). Strikingly, we also demonstrate that Tau regulates the increase in newborn neuron survival triggered by environmental enrichment (EE). Moreover, newborn granule neurons from Tau−/− mice did not show any stimulatory effect of EE on dendritic development or on PSD generation. Thus, our data demonstrate that Tau−/− mice show impairments in the maturation of newborn granule neurons under basal conditions and that they are insensitive to the modulation of adult hippocampal neurogenesis exerted by both stimulatory and detrimental stimuli.

The IDH-Tau-EGFR triad defines diffuse glioma pathology by controlling mesenchymal differentiation and neo-vascular fitness

“…However, this aggregation of Tau compromises its microtubulestabilising functions (loss of physiological function), favoring the evolution of the pathology. In agreement with the loss-of-function model, we have reported behavioral changes and neurogenesis in aged Tau knockout mice (53). Interestingly, EMT genes are enriched in the affected areas of AD brains (54).…”

Endolysosomal degradation of Tau and its role in glucocorticoid‐driven hippocampal malfunction

“…For example, prolonged exposure to stress or high levels of GC trigger Tau accumulation and hyperphosphorylation accompanied by synaptic missorting of Tau and neuronal atrophy (Green et al, 2006;Sotiropoulos et al, 2011;Pinheiro et al, 2015;Lopes et al, 2016c). Importantly, Tau is essential for this stress/GC-driven damage, as Tau ablation was found to be neuroprotective (Lopes et al, 2016c;Pallas-Bazarra et al, 2016;Dioli et al, 2017). While previous in vitro studies showed that GC reduce Tau turnover (Sotiropoulos et al, 2008a), the underlying molecular mechanisms were unclear.…”

“…Furthermore, emerging studies support a crucial role for Tau in diverse brain pathologies (for review, see Sotiropoulos et al, ) including prolonged exposure to stressful conditions, a known risk factor for AD and major depressive disorder (Vyas et al , ). In particular, recent studies demonstrate that exposure to chronic environmental stress or the major stress hormones, glucocorticoids (GC), triggers the accumulation of Tau and its synaptic missorting, precipitating dendritic atrophy and synaptic dysfunction in a Tau‐dependent manner (Pinheiro et al , ; Lopes et al , ,b; Pallas‐Bazarra et al , ; Dioli et al , ). However, the cellular mechanisms responsible for stress/GC‐induced accumulation of Tau remain unclear.…”

Endolysosomal degradation of Tau and its role in glucocorticoid-driven hippocampal malfunction

“…For example, prolonged exposure to stress or high levels of GC trigger Tau accumulation and hyperphosphorylation, accompanied by synaptic missorting of Tau and neuronal atrophy (Green et al, 2006, Lopes et al, 2016c, Pinheiro et al, 2015, Sotiropoulos et al, 2011. Importantly, Tau is essential for this stress/GC-driven damage, as Tau ablation was found to be neuroprotective (Dioli et al, 2017, Lopes et al, 2016c, Pallas-Bazarra et al, 2016. While previous in vitro studies showed that GC reduce Tau turnover , the underlying molecular mechanisms were unclear.…”

“…Furthermore, emerging studies support a crucial role for Tau in diverse brain pathologies (for review, see 8 ) including prolonged exposure to stressful conditions, a known risk factor for AD and major depressive disorder 9 . In particular, recent studies demonstrate that exposure to chronic environmental stress or the major stress hormones, glucocorticoids (GC), triggers the accumulation of Tau and its synaptic missorting, precipitating dendritic atrophy and synaptic dysfunction in a Tau-dependent manner [10][11][12][13][14] . However, the cellular mechanisms responsible for stress/GC-induced accumulation of Tau remain unclear.…”