The recent news on structural studies on Nerve Growth Factor (NGF), in relation to its interaction with the p75 receptor provide important new data. It will help in gaining insight into the emerging role of NGF, its precursor form(s), and of its complex receptor system in neurodegeneration. This growing body of data, together with the recently announced promising results on the pilot clinical trial on gene delivery of NGF to AD patients by the group of Mark Tuszynski, highlight again the central importance of NGF and Alzheimer's disease.
This connection is further strengthened by the Alzheimer-like neurodegeneration observed in the anti NGF AD11 transgenic mice, expressing a recombinant antibody against NGF (Capsoni et al., 2000, 2002a). The complex neurodegenerative phenotype, observed in AD11 mice, goes beyond what would be expected on the sole basis of the interation between NGF and cholinergic neurons in the basal forebrain. The complexity and the subtle and multiple levels of regulation of different NGF forms (including the often overlooked neurotrophin heterodimers) and its multiple receptor system provide a framework to interpret, from a mechanistic point of view, the neurodegeneration resulting from the expression of neutralizing anti NGF antibodies in the AD11 transgenic mice.
Ongoing quantitative biophysical studies of the binding between the alphaD11 anti-NGF antibodies and different processing forms of NGF will help our understand of how anti-NGF antibodies in the brain might alter the complex equilibrium and regulation of NGF and its receptors. Also, ongoing structural studies on these anti NGF antibodies, alone (Covaceuszach et al., 2004) or in combination with NGF, will help elucidate the mechanism of neurodegeneration in AD11 mice. The AD11 mice provide, therefore, an important opportunity
i) to understand how a specific type of neurotrophic deficit can lead to a complex neurodegeneration phenotype, as well as
ii) to develop and test potential therapeutic approaches based on boosting neurotrophic activity and on neuroprotection approaches, in addition to approaches against established AD targets.
In this respect, our group has previously shown that the intranasal delivery of NGF in AD11 mice is effective, within a welld efined time window, at rescueing the neurodegeneration (Capsoni et al, 2002 b). Recent unpublished data (Capsoni et al., unpublished) show that the intranasal administration of NGF is also able to induce a rescue of the cognitive behavioral deficit observed in AD11 mice, in particular those linked to recognition memory (object recognition and memory for context).
In conclusion, we believe that AD11 mice, and other models along these lines that may be derived, will provide new insights into the emerging link between the complexities of NGF processing and signalling and Alzheimer's neurodegeneration. Antonino Cattaneo and Simona Capsoni a.cattaneo@laylinegenomics.coms.capsoni@laylinegenomics.com
References:
Capsoni S, Ugolini G, Comparini A, Ruberti F, Berardi N, Cattaneo A.
Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice.
Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6826-31.
PubMed.
Capsoni S, Giannotta S, Cattaneo A.
Beta-amyloid plaques in a model for sporadic Alzheimer's disease based on transgenic anti-nerve growth factor antibodies.
Mol Cell Neurosci. 2002 Sep;21(1):15-28.
PubMed.
Covaceuszach S, Cassetta A, Cattaneo A, Lamba D.
Purification, crystallization, X-ray diffraction analysis and phasing of a Fab fragment of monoclonal neuroantibody alphaD11 against nerve growth factor.
Acta Crystallogr D Biol Crystallogr. 2004 Jul;60(Pt 7):1323-7.
PubMed.
Capsoni S, Giannotta S, Cattaneo A.
Nerve growth factor and galantamine ameliorate early signs of neurodegeneration in anti-nerve growth factor mice.
Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12432-7.
PubMed.
Comments
The recent news on structural studies on Nerve Growth Factor (NGF), in relation to its interaction with the p75 receptor provide important new data. It will help in gaining insight into the emerging role of NGF, its precursor form(s), and of its complex receptor system in neurodegeneration. This growing body of data, together with the recently announced promising results on the pilot clinical trial on gene delivery of NGF to AD patients by the group of Mark Tuszynski, highlight again the central importance of NGF and Alzheimer's disease.
This connection is further strengthened by the Alzheimer-like neurodegeneration observed in the anti NGF AD11 transgenic mice, expressing a recombinant antibody against NGF (Capsoni et al., 2000, 2002a). The complex neurodegenerative phenotype, observed in AD11 mice, goes beyond what would be expected on the sole basis of the interation between NGF and cholinergic neurons in the basal forebrain. The complexity and the subtle and multiple levels of regulation of different NGF forms (including the often overlooked neurotrophin heterodimers) and its multiple receptor system provide a framework to interpret, from a mechanistic point of view, the neurodegeneration resulting from the expression of neutralizing anti NGF antibodies in the AD11 transgenic mice.
Ongoing quantitative biophysical studies of the binding between the alphaD11 anti-NGF antibodies and different processing forms of NGF will help our understand of how anti-NGF antibodies in the brain might alter the complex equilibrium and regulation of NGF and its receptors. Also, ongoing structural studies on these anti NGF antibodies, alone (Covaceuszach et al., 2004) or in combination with NGF, will help elucidate the mechanism of neurodegeneration in AD11 mice. The AD11 mice provide, therefore, an important opportunity
i) to understand how a specific type of neurotrophic deficit can lead to a complex neurodegeneration phenotype, as well as
ii) to develop and test potential therapeutic approaches based on boosting neurotrophic activity and on neuroprotection approaches, in addition to approaches against established AD targets.
In this respect, our group has previously shown that the intranasal delivery of NGF in AD11 mice is effective, within a welld efined time window, at rescueing the neurodegeneration (Capsoni et al, 2002 b). Recent unpublished data (Capsoni et al., unpublished) show that the intranasal administration of NGF is also able to induce a rescue of the cognitive behavioral deficit observed in AD11 mice, in particular those linked to recognition memory (object recognition and memory for context).
In conclusion, we believe that AD11 mice, and other models along these lines that may be derived, will provide new insights into the emerging link between the complexities of NGF processing and signalling and Alzheimer's neurodegeneration. Antonino Cattaneo and Simona Capsoni a.cattaneo@laylinegenomics.com s.capsoni@laylinegenomics.com
References:
Capsoni S, Ugolini G, Comparini A, Ruberti F, Berardi N, Cattaneo A. Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6826-31. PubMed.
Capsoni S, Giannotta S, Cattaneo A. Beta-amyloid plaques in a model for sporadic Alzheimer's disease based on transgenic anti-nerve growth factor antibodies. Mol Cell Neurosci. 2002 Sep;21(1):15-28. PubMed.
Covaceuszach S, Cassetta A, Cattaneo A, Lamba D. Purification, crystallization, X-ray diffraction analysis and phasing of a Fab fragment of monoclonal neuroantibody alphaD11 against nerve growth factor. Acta Crystallogr D Biol Crystallogr. 2004 Jul;60(Pt 7):1323-7. PubMed.
Capsoni S, Giannotta S, Cattaneo A. Nerve growth factor and galantamine ameliorate early signs of neurodegeneration in anti-nerve growth factor mice. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12432-7. PubMed.
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