Essential role of tau phosphorylation in adult hippocampal neurogenesis.
An increased hippocampal neurogenesis has been observed in Alzheimer disease (AD), the most common neurodegenerative disorder characterized with accumulation of β-amyloid (Aβ) and hyperphosphorylated tau (p-tau). Studies in transgenic mouse models suggest that the amyloidosis suppresses adult neurogenesis. Although emerging evidence links tau to neurodevelopment, the direct data regarding tau phosphorylation in adult neurogenesis is missing. Here, we found that the immature neurons, identified by doublecortin (DCX) and neurogenic differentiation factor (neuroD), were only immunoreactive to p-tau but not to the non-p-tau in adult rat brain and human patients with AD, and the p-tau was coexpressed temporally and spatially with DCX and neuroD in the hippocampal dentate gyrus (DG) of the rat brains during postnatal development. A correlative increase of immature neuron markers and tau phosphorylation was induced in rat hippocampal DG by upregulating glycogen synthase kinase-3 (GSK-3), a crucial tau kinase, and the increased neurogenesis was due to an enhanced proliferation but not survival or differentiation of the newborn neurons. The hippocampal neurogenesis was severely impaired in tau knockout mice and activation of GSK-3 in these mice did not rescue the deficits. These results reveal an essential role of tau phosphorylation in adult hippocampal neurogenesis. It suggests that spatial/temporal manipulation of tau phosphorylation may be compensatory for the neuron loss in neurological disorders, including AD.
Hong
Xiao-Ping
XP
Department of Pathophysiology, Key Laboratory of Neurological Diseases of Education Committee of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Peng
Cai-Xia
CX
Wei
Wei
W
Tian
Qing
Q
Liu
Ying-Hua
YH
Yao
Xiu-Qing
XQ
Zhang
Yao
Y
Cao
Fu-Yuan
FY
Wang
Qun
Q
Wang
Jian-Zhi
JZ
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D000089662:Doublecortin Protein; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016875:tau Proteins / Q000378:metabolism*
C000714847:Dcx protein, mouse; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D016875:tau Proteins