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SAGE KE Bulletin Board

Neurogenesis in Alzheimer's Disease: Highlights from the 35th Annual Meeting in Washington, DC

25 November 2005

Sergey Larionov

There is extensive evidence indicating that new neurons are generated in the dentate gyrus of the adult mammalian hippocampus, a region of the brain that is important for learning, memory, and mood control (1-5) – all of which are adversely affected in Alzheimer's disease (AD). However, it was not known whether these new neurons become functional, as the methods used to study adult neurogenesis were limited to fixed tissue (6). Hippocampal neurogenesis has been observed in adult animals from birds to humans (1-7). The newly generated cells may have a function in cognition and brain repair.

Neurogenesis, which persists in the adult mammalian brain, may provide a basis for neuronal replacement therapy in neurodegenerative diseases like AD (8). Neurogenesis is increased in certain acute neurological disorders, such as ischemia and epilepsy, but the effect of more chronic neurodegeneration is uncertain, and some animal models of AD show impaired neurogenesis. There is also evidence in studies with cultured cells suggesting that amyloid plaques, a key feature of AD, may impair neurogenesis (9). For technical reasons, researchers have not been able to determine whether neurogenesis is, indeed, impaired in the Alzheimer brain.

The integrity of neurogenesis in the adult hippocampus in Familial Alzheimer's disease (FAD) is uncertain. Studies of neurogenesis in transgenic mouse models of FAD have yielded conflicting results, and are complicated by the use of heterologous promoters that drive high-level overexpression of mutant proteins in terminally differentiated neurons, but not in the neural stem and progenitor cell populations themselves. As an alternative approach for studying the fidelity of hippocampal neurogenesis in FAD, C. Zhang et al. (10) examined mice bearing knock-in mutations in APP or PS-1, or both, in which FAD-linked mutations were introduced into their endogenous genes. Progenitor cells immunopositive for mini chromosome maintenance protein 2 (MCM2) and immature neurons immunopositive for doublecortin were quantified in the subgranular zone of the dorsal hippocampus for mice bearing the Swedish APP knock-in mutation that were either wild-type for PS-1, heterozygous for the PS-1 P264L FAD- linked knock-in mutation, or homozygous for mutant PS-1. In comparison with PS-1 wild-type and heterozygous mutants, the PS-1 homozygous mutant mouse contained three-fold fewer MCM2-positive neural progenitor cells and two-fold fewer doublecortin-positive immature neurons at 9 months of age. The decrease in differentiating neurons was confirmed by immunoblot quantitation of hippocampal doublecortin content. Of the three genotypes, only the APP/PS-1 double homozygous knock-in mutant mouse developed amyloid pathology in the hippocampal dentate gyrus by this age.

O. Butovsky et al. (11) observed an enhanced neurogenesis in the dentate gyrus of a triple-transgenic mouse model of AD. Inflammation- associated (LPS- or A -activated) microglia block both neurogenesis and oligodendrogenesis of adult rodent neural progenitor cells (NPCs), whereas microglia activated by IL-4 induce cell renewal. Blockage and induction correlated with up- and down-regulation, respectively, of microglial TNF- production. The significance of IL-4-activated microglia for neural cell renewal in vivo was demonstrated following their injection into the lateral ventricles.

In summary, FAD-linked PS-1 gene mutations impair neurogenesis in the adult hippocampus, and suggest a novel mechanism linking amyloid deposition to dysfunctional hippocampal neuroplasticity and, potentially, to cognitive and behavioral abnormalities of AD. Moreover, IL-4-activated microglia is able to support neurogenesis in a triple-transgenic mouse model of AD. Thus, immune modulation provides an interesting mechanism to support neuronal repair.

References:

1. Altman, J., and Das, G. D. Autoradiographic and histological evidence of postnatal neurogenesis in rats. J. Comp. Neurol. 124, 319-335 (1965). . 2. Kaplan, M. S., and Hinds, J. W. Neurogenesis in the adult rat: electron microscopic analysis of light radioautographs. Science 197, 1092- 1094 (1977).

3. Kuhn, H. G., Dickinson-Anson, H., and Gage, F. H. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J. Neurosci. 16, 2027-2033 (1996).

4. Kornack, D. R., and Rakic, P. Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc. Natl Acad. Sci. USA 96, 5768-5773 (1999).

5. Eriksson, P. S. et al. Neurogenesis in the adult human hippocampus. Nature Med. 4, 1313-1317 (1998).

6. van Praag, H., Schinder A.F., Christie, B.R., Toni, N., Palmer T.D., and Gage, F.H. Functional neurogenesis in the adult hippocampus Nature 415, 1030–1034 (28 February 2002)

7. Barnea, A., and Nottebohm, F. Seasonal recruitment of hippocampal neurons in adult free-ranging black-capped chickadees. Proc. Natl Acad. Sci. USA 91, 11217-11221 (1994).

8. Jin K, Peel A.L., Mao, X.O., Xie L., Cottrell B.A., Henshall D.C., and Greenberg D.A. Increased hippocampal neurogenesis in Alzheimer's disease. Proc. Natl Acad. Sci. USA 101, 343-347 (2004).

9. He, F., Ge, W., Martinowich K., Becker-Catania, S., Coskun V., Zhu, W., Wu, H., Castro, D, Guillemot, F., Fan, G., de Vellis, G., and Sun, Y.E. A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis. Nature Neuroscience 8, 616 - 625 (2005)

10. Zhang, C., Dressler, L., Salidas, S., and Siman, R. IMPAIRED NEUROGENESIS WITH AMYLOID DEPOSITION IN THE ADULT HIPPOCAMPUS IN THE APP/PRESENILIN DOUBLE KNOCK-IN MUTANT MOUSE Program No. 83.11. (2005)

11. Butovsky, O., Landa, G., Ziv, Y., Avidan, H., Kunis, G., Greenberg, N., Schwartz, A., Smirnov, I., and Schwartz, M. IL-4-ACTIVATED MICROGLIA SUPPORT NEUROGENESIS AND OLIGODENDROGENESIS IN RODENT MODELS OF ALZHEIMER'S DISEASE AND MULTIPLE SCLEROSIS Program No. 442.1. (2005)


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