. Stimulation of endogenous neurogenesis by anti-EFRH immunization in a transgenic mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2007 Jan 30;104(5):1691-6. PubMed.

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  1. This paper presents the interesting finding that immunization of the PDAPP mouse model of AD with the EFRH sequence of Aβ promotes neurogenesis. While many reports using the Aβ immunotherapy approach have focused on more classical AD-type pathological features (Aβ levels, cerebral amyloidosis, gliosis, etc.), this paper suggests that neurogenesis may contribute to the beneficial effects of the Aβ vaccine.

    The authors propose that mitigating the effects of AD-type neurotoxicity and cognitive function by restoring the neuronal population may promote recovery from AD. Regarding their results in mice, the authors clearly show increased BrdU+NeuN+ cells in response to EFRH immunization. Further, they show that these cells are also positive for Zif268, a marker of synaptic function. I agree with Dr. Greenberg's comment above that a case for functionality would be much stronger in the presence of positive cognitive/behavioral data. Given the current hot debate over the potential (therapeutic) importance of adult neurogenesis, one wonders whether new neurons could actually take the place (i.e., form meaningful synaptic connections) of dysfunctional, dying, and/or dead neurons in AD. It is important to note that the PDAPP mouse model of AD does not manifest appreciable neuronal loss. If these new neurons are indeed functional, could the authors speculate (or maybe they have data) on how these new neurons are taking over for dysfunctional neurons in the PDAPP mice?

    View all comments by Terrence Town
  2. This very interesting paper reports that treatment with an antibody against the EFRH sequence of β amyloid increases neurogenesis in the brains of mice carrying a mutant gene for amyloid precursor protein found in some patients with familial Alzheimer disease (AD).

    This finding is of interest because it suggests that immunotherapy for AD might not only mobilize and remove amyloid from the brain, but also stimulate the production of new neurons, which could contribute to brain repair.

    An important caveat in interpreting these findings is that, although newborn neurons in the brains of antibody-treated mice showed evidence of being functional cells, there is no evidence as yet that this improved behavioral or cognitive deficits in the mouse model.

    Another interesting aspect of the study is that neurogenesis induced by EFRH immunization was found throughout the brain, and was not restricted to the classic neuroproliferative zones of the adult brain—dentate gyrus and subventricular zone. This means that either that newborn neurons arising in these regions migrated extensively in response to AD pathology, or that many more areas can give rise to new neurons in the diseased than in the normal brain.

    Finally, the fact that clearing amyloid increased neurogenesis argues that amyloid itself may not be the trigger for the increased neurogenesis observed in some mouse models of AD. This would be consistent with the previous observation that the increase in neurogenesis in these animals precedes the onset of amyloid deposition.

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