Hippocampal Neurogenesis Is Enhanced in Adult Tau Deficient Mice

Abstract

Tau dysfunction is common in several neurodegenerative diseases including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Affective symptoms have often been associated with aberrant tau pathology and are commonly comorbid in patients with tauopathies, indicating a connection between tau functioning and mechanisms of depression. The current study investigated depression-like behavior in Mapt−/− mice, which contain a targeted deletion of the gene coding for tau. We show that 6-month Mapt−/− mice are resistant to depressive behaviors, as evidenced by decreased immobility time in the forced swim and tail suspension tests, as well as increased escape behavior in a learned helplessness task. Since depression has also been linked to deficient adult neurogenesis, we measured neurogenesis in the hippocampal dentate gyrus and subventricular zone using 5-bromo-2-deoxyuridine (BrdU) labeling. We found that neurogenesis is increased in the dentate gyrus of 14-month-old Mapt−/− brains compared to wild type, providing a potential mechanism for their behavioral phenotypes. In addition to the hippocampus, an upregulation of proteins involved in neurogenesis was observed in the frontal cortex and amygdala of the Mapt−/− mice using proteomic mass spectrometry. All together, these findings suggest that tau may have a role in the depressive symptoms observed in many neurodegenerative diseases and identify tau as a potential molecular target for treating depression.

The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics

“…Tau knockdown also delays neuronal maturation in primary neurons [ 54 ] and induces transcriptional repression of neuronal genes [ 11 ], indicative of a potential role of tau in promoting neuronal differentiation. Some studies, however, contradict these findings, reporting increased neurogenesis in tau-deficient animals [ 50 ]. Further exploration of the role of tau in adult neurogenesis, and whether this translates to humans, is, therefore, required.…”

Liquid–liquid phase separation of tau: From molecular biophysics to physiology and disease

“…In vitro and in vivo studies further demonstrated the involvement of tau in the regulation of gene expression, 50 spine growth, 51 and neuron maturation 52 . Some of these activities of tau, however, have been challenged 53–55 …”

Tau Pathology and Adult Hippocampal Neurogenesis: What Tau Mouse Models Tell us?

“…Distinct time point of analysis could lead to data variation ( 98 ). A remarkable sex difference was observed in AHN of rodent brains ( 75 , 99 ). Furthermore, data variability may be caused by the sensitivities of antibodies used for detection ( 29 ).…”

“…A significant reduction of DCX- and NeuroD- positive neuroblast cells in tau knockout mice was observed ( 62 ). On the contrary, Criado-Marrero et al have recently reported that BrdU-positive newborn cells and DCX-positive immature neurons were increased in the DG and SVZ of tau knockout mice at 14 months ( 75 ). Yet, other two independent studies have reported that DCX-labeled neuroblast cell number was not altered in the DG of adult tau knockout mice ( 71 , 74 ).…”