Impact of N-tau on adult hippocampal neurogenesis, anxiety, and memory

Abstract

This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. a b s t r a c tDifferent pathological tau species are involved in memory loss in Alzheimer's disease, the most common cause of dementia among older people. However, little is known about how tau pathology directly affects adult hippocampal neurogenesis, a unique form of structural plasticity implicated in hippocampusdependent spatial learning and mood-related behavior. To this aim, we generated a transgenic mouse model conditionally expressing a pathological tau fragment (26e230 aa of the longest human tau isoform, or N-tau) in nestin-positive stem/progenitor cells. We found that N-tau reduced the proliferation of progenitor cells in the adult dentate gyrus, reduced cell survival and increased cell death by a caspase3eindependent mechanism, and recruited microglia. Although the number of terminally differentiated neurons was reduced, these showed an increased dendritic arborization and spine density. This resulted in an increase of anxiety-related behavior and an impairment of episodic-like memory, whereas less complex forms of spatial learning remained unaltered. Understanding how pathological tau species directly affect neurogenesis is important for developing potential therapeutic strategies to direct neurogenic instructive cues for hippocampal function repair.

Chronic cerebral hypoperfusion causes decrease of O-GlcNAcylation, hyperphosphorylation of tau and behavioral deficits in mice

“…Taken together, these findings suggest that CCH leads to decreased O-GlcNAcylation and then hyperphosphorylation of tau. Abnormally hyperphosphorylated tau might also contribute to the increased anxiety observed in the CCH mice since a link between anxiety-related behavior and tau hyperphosphorylation was reported previously (Pristera et al, 2013). …”

Correcting miR92a-vGAT-Mediated GABAergic Dysfunctions Rescues Human Tau-Induced Anxiety in Mice

“…22,23 In the AD-related APP or APP/PS1 models, some show anxiety, 24,25 others do not, [26][27][28] whereas the 3XTg mice, which overexpress tau and APP/PS1, show significant anxiety behaviors, 29,30 suggesting a more intimate connection between tau and anxiety. In transgenic mice with conditional expression of N-terminal tau in nesting-positive cells, the anxiety behavior was also shown, 31 which provides direct evidence supporting the role of tau in anxiety. However, the mechanisms underlying tau-involved anxiety are not clear, and there is currently no intervention.…”

Exercise as a pro-cognitive, pro-neurogenic and anti-inflammatory intervention in transgenic mouse models of Alzheimer’s disease

“…Cognitive function and anxiety behaviours were assessed in an inducible mouse model facilitating overexpression of N-tau in nestin + neural precursor cells (NPCs). Mice in which N-tau was overexpressed exhibited a heightened anxiety profile and also performed worse in the MWM compared to control mice (Pristera et al, 2013). These behavioural changes were accompanied by significant reductions in cell proliferation, neurogenesis and cell survival, as well as an increase in cell death and microglial activation.…”