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

Abstract

Adult hippocampal neurogenesis (AHN) has been widely confirmed in mammalian brains. A growing body of evidence points to the fact that AHN sustains hippocampal-dependent functions such as learning and memory. Impaired AHN has been reported in post-mortem human brain hippocampus of Alzheimer's disease (AD) and is considered to contribute to defects in learning and memory. Neurofibrillary tangles (NFTs) and amyloid plaques are the two key neuropathological hallmarks of AD. NFTs are composed of abnormal tau proteins accumulating in many brain areas during the progression of the disease, including in the hippocampus. The physiological role of tau and impact of tau pathology on AHN is still poorly understood. Modifications in AHN have also been reported in some tau transgenic and tau-deleted mouse models. We present here a brief review of advances in the relationship between development of tau pathology and AHN in AD and what insights have been gained from studies in tau mouse models.

Keywords: Alzheimer's disease; dentate gyrus; neurogenesis; tau; tauopathy.

Figure 1

(A–C) Representative photos of tau pathology detected in the DG of post-mortem brain section of a 65-year-old male AD patient (Braak VI). Tau pathology was detected by anti-total tau B19 antibody (9) (A), anti-phospho Ser396/404 tau PHF1 antibody (10) (B), or by Gallyas silver staining (11) (C). (D) Representative photo of tau pathology detected by PHF1 in the DG of 12-month-old tau Tg30 mice (12). ML, molecular layer; GCL, granule cell layer; SGZ, subgranular zone. (E) Specific markers for five different stages of AHN in the dentate gyrus of the hippocampus. GFAP, glial fibrillary acidic protein; BLBP, brain lipid-binding protein; SOX2, SRY (sex determining region Y)-box 2; DCX, doublecortin; 3R tau, tau with 3 repeats of microtubule-binding sequences; NeuN, neuronal nuclei; 4R tau, tau with 4 repeats of microtubule-binding sequences. (F) Schematic representation of the human 6 isoforms of tau protein. Exon 2, 3, and 10 (E2, E3, and E10, respectively) are alternatively spliced. Alternative splicing leads to 0, 1 or 2 inserts near amino terminus (0N, 1N, or 2N, respectively) and 3 or 4 repeats (3R or 4R, respectively) of microtubule-binding sequences near carboxyl terminus. The shortest 0N3R isoform is predominantly detected in immature neurons of fetal brains and of adult hippocampus. While only 4R isoforms are principally expressed in adult mouse brains, all the 6 isoforms are expressed in adult human brains. (G) Immunostaining of immature neurons by anti-3R tau RD3 antibody (Merck Millipore #05-803) in the dentate gyrus of the hippocampus in a 12-month-old wild-type mouse. (H) Functional involvement of tau at different stages of AHN. Hematoxylin counterstaining for (A–D,G). Detailed protocol on histological analyses is available in (12). Scale bars: 25 μm.