Before getting too excited about research findings in animals, AD researchers want to see similar data from human beings. An article in the September 7 issue of PNAS does the opposite, showing evidence of increased neurogenesis in an animal model of Alzheimer disease that supports results obtained from humans.

Late in 2003, David Greenberg, Kunlin Jin, and colleagues at Buck Institute for Aging in Novato, California, reported that they had found, in autopsy tissue of confirmed AD cases, increased expression of a number of immature neuron markers in the proliferative area of the hippocampus—the dentate gyrus's subgranular zone (DG-SGZ) (see ARF related news story).

First author Jin and colleagues now report on the birth of new neural cells in mice that carry both the Swedish (K595N/M596L) and Indiana (V717F) mutations that cause early onset AD. The researchers counted newly born cells, as determined by BrdU labeling, in the DG-SGZ of three-month-old and one-year-old mice. At both ages, the transgenic mice had about twice the number of new cells as did wild-type littermates. In support of the case that these are new neurons, the researchers report finding them labeled with markers for the proteins doublecortin and Neuro D, both found in immature neurons.

By contrast, in the other brain area of adult neural proliferation, the subventricular zone, the researchers found increased BrdU labeling, as well as doublecortin and Neuro D, at one year of age, but not in the younger mice. The authors suggest that this difference may reflect the fact that the hippocampus is one of the areas where AD pathology first makes its appearance.

Jin and colleagues point out that their current study helps argue against some of the possible confounds in their study of human AD tissue. For example, the new findings militate against the possibility that nutritional deficiency—which occurs in late AD and which boosts neurogenesis in animals—might have led to increased neurogenesis. Similarly, cholinesterase inhibitors, memantine, statins, or nonsteroidal antiinflammatory drugs—all linked to increased neurogenesis and all potential confounds in human AD—were not present in the animals.

One question the results bring up is why increased neurogenesis would occur in three-month-old mice, where there is no evidence of the cell loss seen in older APPSw/Ind mice. The authors point out that this phenomenon has been described in an experimental model of epilepsy, and offer up the possibility that some other disease-associated pathology, such as defective neurotransmission, triggers neurogenesis.

The researchers are especially interested in defective neurotransmission because it may help explain why this study found increased hippocampal neurogenesis in AD transgenic mice, while other studies found impaired neurogenesis. The authors suggest that perhaps the addition of the Indiana (V717F) mutation made the difference. Describing one possible effect of the Indiana mutation on proliferation, Jin and colleagues note that by itself this mutation produces defects in synaptic transmission, and when combined with the Swedish mutation, it contributes to even larger synaptic defects (Hsia et al., 1999). Since hippocampal glutamatergic pathways are affected early in AD, and also in these double-transgenic mice, the authors suggest the possibility that, "a defect in glutamatergic transmission is what triggers neurogenesis in [APPSw,Ind] mice and patients with AD."—Hakon Heimer

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  1. This paper is a continuation of a study the authors published in the same journal.

    In their previous paper, they stated that transgenic mice expressing mutant forms of APP (22, 23) or presenilin-1 (41) show impaired, rather than increased, neurogenesis. They further stated that it is impossible to predict whether animal models that may more closely resemble AD may have enhanced neurogenesis, because none of these models fully reproduces the features of familial AD, and the molecular stimulus to neurogenesis in AD is unknown.

    In the current study, they used APPSw/Ind transgenic mice, and indicate that the addition of Indiana mutation to APP produces contradictory results compared to the previous studies. They suggested that synaptic abnormalities, which can be found in this APP transgenic mouse, and further, a defect in glutamatergic transmission, may be the stimulus for neurogenesis. However, these kinds of changes may occur in other types of APP transgenic mice, and it is difficult to explain why enhanced neurogenesis occurred only in the APPSw/Ind transgenic animals.

    Another consideration is that the BrdU positive nuclei indicate only proliferation of cells. Although these are most likely stem cells in normal control brain, it may not be the case under pathological conditions. Namely, glia may proliferate at significant levels in aged APP transgenic mice. Thus, analysis of other stem cell markers or quantification of newly born neurons may be desirable.

    This study may not be conclusive, and further studies are necessary in order to understand stem cell biology under AD pathology.

  2. The concept of AD increasing neurogenesis is extremely interesting, and the proposal that this may be a compensatory response plausible. These findings directly disprove an alternative hypothesis: that the memory deficits of AD are related to the clinical phenomenon of "chemo brain," in which patients undergoing chemotherapy and consequent probable disruption of neurogenesis exhibit memory deficits.

    View all comments by Paul Coleman

References

News Citations

  1. New Neurons Born among the Dying in Alzheimer’s Hippocampus?

Paper Citations

  1. . Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3228-33. PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. . Enhanced neurogenesis in Alzheimer's disease transgenic (PDGF-APPSw,Ind) mice. Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13363-7. PubMed.