25 Jan 2007

A second immunotherapy-themed paper this week (see ARF related news story) describes an unanticipated effect of Aβ immunization in mice. In the January 22 PNAS online, Beka Solomon and colleagues from Tel Aviv University in Israel report that vaccinated AD mice display a threefold increase in the production of new neurons from progenitors in several areas of the brain. While the basis for this spurt in neurogenesis is not clear, the results raise the question of whether immunotherapy might have benefits beyond simply clearing out amyloid, such as balancing neuronal loss with the birth of new neurons.

In past work, Solomon and colleagues developed an amyloid vaccine using a four-amino-acid peptide sequence derived from the extreme N-terminus of Aβ (EFRH, residues number 3-6). The antibody blocks Aβ aggregation, and vaccination with the epitope reduced plaques and AD pathology and improved cognitive performance in an APP/PS1 double-transgenic mouse model of AD (Lavie et al., 2004).

In the new report, coauthors Maria Becker and Vered Lavie measured neurogenesis in vaccinated mice by injecting 3H-bromodeoxyuridine, waiting 41 days, and then looking for labeled cells in postmortem brain samples. They saw the label incorporated into cells in the ventricle lining and the subventricular zone, both expected locations for newborn neurons. In addition, they found BrDU-positive cells in the cortex, hippocampus, and optic track. In all, the number of labeled cells was three times higher in vaccinated than in unvaccinated animals. More of them were neurons: In vaccinated mice, 90 percent of the BrDU labeled cells also expressed the neuron marker NeuN, compared to 63 percent in unvaccinated mice. The new cells appeared to be functional, the authors believe, because most expressed the activation-dependent gene Zif268. In all, immunization appears to promote the production and maturation of neuronal progenitors in PDAPP mice, the authors suggest.

The results don’t say why immunization would do that. One possibility the authors consider is that soluble Aβ peptide released by disaggregating antibodies would exert a direct neurotrophic effect. This effect of Aβ is controversial but has been proposed independently before (see comments to Lopez-Toledano et al., 2004). Alternatively, the antibodies might neutralize toxic Aβ, or reduce neuroinflammation, which could be preventing normal neurogenesis.

Another open question is whether increased neurogenesis is a general response to immunization with Aβ, or specific to certain peptides. Solomon told ARF, “I don’t know if this response is unique for EFRH, but the peptide sequence is in a key position for Aβ conformational change. Moreover, the running clinical immunological trials—active or passive—are based on this region. I do believe that a low but continuous flow of anti-EFRH antibodies will have beneficial effects in treated patients.”

Previously, other researchers have tracked neurogenesis in these mice, and found an age-related decrease in progenitor proliferation in the subgranular zone of the hippocampus compared to control mice (Donovan et al., 2006). The authors of that report speculated that altered neurogenesis might contribute to age-related cognitive deficits. On the flip side of that, Solomon and coworkers write that in immunized mice, “The improvement in memory and learning, combined with alleviation of the neurotoxic amyloid burden and the pathology associated with it, may reflect functional neurogenesis induced by the anti-Aβ peptide immunization.”

Both conclusions jump the gun, according to a perspective on neurogenesis in the January 19 issue of Science. In that piece, Helen Scharfman and Rene Hen of Columbia University argue that the clinical relevance of neurogenesis remains mostly unknown. They urge their colleagues to evaluate carefully a simplistic view that boosting neuron production will automatically have beneficial effects in a wide range of neurological or neurodegenerative diseases. The observed stimulation of neurogenesis after injury or insult could be restorative, but only if the new neurons are long-lived and integrate into existing circuits. In some cases, increased neurogenesis may actually be harmful; for example, in temporal lobe epilepsy, seizure-induced bursts of neurogenesis may contribute to persistent seizures in animal models and perhaps also in humans. Furthermore, claims that a growing number of drugs including antidepressants, mood stabilizers, and the cognitive enhancers galantamine and memantine benefit the brain by stimulating neurogenesis need to be rigorously examined, Scharfman and Hen add. While there is some evidence that neurogenesis is required for the actions of the antidepressants, for the other drugs the jury is still out.

Within the AD field, debate continues about the role of neurogenesis in environmental enrichment, an intervention shown to reduce amyloid pathology. Last year, Hen and colleagues found no role for neurogenesis in behavioral effects of enrichment, while other investigators find just the opposite (see ARF related news story).—Pat McCaffrey

Comments

1. • David Greenberg
     
   • Posted: 25 Jan 2007
   • Paper: Stimulation of endogenous neurogenesis by anti-EFRH immunization in a transgenic mouse model of Alzheimer's disease.

   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.

   View all comments by David Greenberg
2. • Terrence Town
     University of Southern California
   • Posted: 30 Jan 2007

   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

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References

News Citations

1. Immunotherapy Update: Toward Patches and Creams 25 Jan 2007
2. Neurogenesis Not Needed for Environmental Enrichment Effects 29 Apr 2006

Paper Citations

1. Lavie V, Becker M, Cohen-Kupiec R, Yacoby I, Koppel R, Wedenig M, Hutter-Paier B, Solomon B. EFRH-phage immunization of Alzheimer's disease animal model improves behavioral performance in Morris water maze trials. J Mol Neurosci. 2004;24(1):105-13. PubMed.
2. López-Toledano MA, Shelanski ML. Neurogenic effect of beta-amyloid peptide in the development of neural stem cells. J Neurosci. 2004 Jun 9;24(23):5439-44. PubMed.
3. Donovan MH, Yazdani U, Norris RD, Games D, German DC, Eisch AJ. Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease. J Comp Neurol. 2006 Mar 1;495(1):70-83. PubMed.

Further Reading

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