Is the cycle of life—new lives born even as the old die—to be found in the hippocampus of Alzheimer's patients? A study in this week’s online PNAS suggests just this, and poses the question of whether we could spur newly born neurons to replace those that are degenerating.

At the Buck Institute for Aging Research in Novato, California, David Greenberg, Kunlin Jin, and their colleagues compared AD and non-AD brain tissue for levels of molecules that are expressed in immature neurons. They found that AD hippocampus contains significantly higher expression of doublecortin, polysialylated nerve cell adhesion molecule (PSA-NCAM), neurogenic differentiation factor (NeuroD), and TUC-4.

In particular, they found that expression of doublecortin and TUC-4 was associated with neurons in the proliferative zone of the dentate gyrus and in the ultimate home of these cells—the granule cell layer—as well as in the CA1 region of Ammon’s horn, a principal site of hippocampal pathology in AD.

"These findings suggest that neurogenesis is increased in AD hippocampus, where it may give rise to cells that replace neurons lost in the disease, and that stimulating hippocampal neurogenesis might provide a new treatment strategy," write the authors.

Addressing possible objections, the authors note that it is unlikely they were simply observing the effects of brain atrophy. For example, actin expression was unchanged, whereas levels of the immature neuronal markers varied with disease severity and anatomical location, among other factors.

Another concern is that transgenic models of AD have shown the opposite, namely, a diminution of neurogenesis. Noting that these models all fail to recapitulate AD fully, the authors suggest it will be interesting to test whether more recent models, such as the APP/tau mice, might show increased neurogenesis.—Hakon Heimer.

Reference:
Jin K, Peel AL, Mao XO, Lin X, Cottrell B, Henshall DC, Greenberg DA. Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci U S A. 2003 Dec 5 [Epub ahead of print] Abstract

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  1. For stem cell researchers, this is an encouraging report which
    indicates neurogenesis in the Alzheimer's disease (AD) patient's brain.
    If this finding is true, just increasing the stem cell population in the
    patient’s brain might help to regenerate dying neurons in AD. Since we
    have a small-molecule compound that increases endogenous stem cell
    population about sixfold in 27-month-aged rats by peripheral injection, we may be able to develop an application for this drug in AD
     treatment.

    However, as the author pointed out, APP- or PS-mutant
    transgenic mice show impaired rather than increased
    neurogenesis. Such a conflict may come from the different patient
    populations, namely, sporadic and familial AD, meaning if they analyze
    familial AD they might find different results. Furthermore, their best
    clear finding is an increased level of PSA-NCAM in severe AD cases,
    and PSA-NCAM is not necessarily a marker for neuronal progenitors
    because it is also expressed in reactive astrocytes (Nomura et al., 2000). Thus, we may be able to say that AD brain is still trying to regenerate its neurons, but we need further investigation to confirm if spontaneous neurogenesis really occurs in AD.

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References

Paper Citations

  1. . Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):343-7. PubMed.

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Papers

  1. . Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):343-7. PubMed.

Primary Papers

  1. . Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):343-7. PubMed.