title: Human tau expression reduces adult neurogenesis in a mouse model of tauopathy.
abstract: Accumulation of hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT) is a central feature of a class of neurodegenerative diseases termed tauopathies. Notably, there is increasing evidence that tauopathies, including Alzheimer's disease, are also characterized by a reduction in neurogenesis, the birth of adult neurons. However, the exact relationship between hyperphosphorylation and aggregation of MAPT and neurogenic deficits remains unclear, including whether this is an early- or late-stage disease marker. In the present study, we used the genomic-based hTau mouse model of tauopathy to examine the temporal and spatial regulation of adult neurogenesis during the course of the disease. Surprisingly, hTau mice exhibited reductions in adult neurogenesis in 2 different brain regions by as early as 2 months of age, before the development of robust MAPT pathology in this model. This reduction was found to be due to reduced proliferation and not because of enhanced apoptosis in the hippocampus. At these same time points, hTau mice also exhibited altered MAPT phosphorylation with neurogenic precursors. To examine whether the effects of MAPT on neurogenesis were cell autonomous, neurospheres prepared from hTau animals were examined in vitro, revealing a growth deficit when compared with non-transgenic neurosphere cultures. Taken together, these studies provide evidence that altered adult neurogenesis is a robust and early marker of altered, cell-autonomous function of MAPT in the hTau mouse mode of tauopathy and that altered adult neurogenesis should be examined as a potential marker and therapeutic target for human tauopathies.
authors: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, NC30, 9500 Euclid Avenue, Cleveland, OH, USA.
authors: Yutaro
authors: Y
authors: Komuro
authors: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, NC30, 9500 Euclid Avenue, Cleveland, OH, USA.
authors: Guixiang
authors: G
authors: Xu
authors: Department of Molecular Genetics and Microbiology, MIND Institute, University of New Mexico, MSC08 4660, 1 University of New Mexico, Albuquerque, NM, USA.
authors: Kiran
authors: K
authors: Bhaskar
authors: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, NC30, 9500 Euclid Avenue, Cleveland, OH, USA. Electronic address: lambb@ccf.org.
authors: Bruce T
authors: BT
authors: Lamb
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015870:Gene Expression / Q000235:genetics* / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics* / Q000502:physiology*; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000166:cytology; D010766:Phosphorylation; D066263:Protein Aggregation, Pathological; D024801:Tauopathies / Q000473:pathology / Q000503:physiopathology*; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins
keywords: Adult neurogenesis; MAPT; Mouse; Tau; Tauopathy; hTau