NGF, Galantamine Rescue Anti-NGF Model of Alzheimer's

In a transgenic mouse that lacks sufficient nerve growth factor (NGF) and suffers from an AD-like syndrome, NGF or a cholinergic agonist were able to reduce subsets of the pathology, according to a report by Antonino Cattaneo and colleagues in the September 17 Proceedings of the National Academy of Sciences, currently available online.

The mouse model, called AD11, was created to explore the possibility that the death of basal forebrain cholinergic neurons in Alzheimer's disease is related to reductions in nerve growth factor levels. Since creating these mice (by inserting a gene that expresses an anti-NGF antibody, see Ruberti et al. 2000), Cattaneo and his colleagues at the International School for Advanced Studies in Trieste, Italy, have described how the depletion of extracellular NGF in this model recapitulates features of Alzheimer's disease. The AD11 mouse shows neuronal loss, tau hyperphosphorylation and insolubility, neurofibrillary tangle-like abnormalities, and behavioral deficits linked to cholinergic atrophy (Capsoni et al., 2000). It also exhibits amyloid plaques (from the endogenous mouse amyloid precursor protein) (Capsoni et al. 2002), and deficits in cortical synaptic plasticity ( Pesavento et al. 2002), all of which lead Cattaneo and associates to propose this mouse as "a comprehensive model for sporadic AD."

In the current paper, the researchers explored whether treatment with NGF or with the cholinergic agonist galantamine could ameliorate the neurodegeneration and cholinergic deficit in the AD11 mice. Both intranasally delivered NGF and intraperitoneal galantamine were able to prevent a cholinergic deficit from developing in the basal forebrain, but only NGF was able to prevent hyperphosphorylation in entorhinal cortex neurons. Conversely, galantamine, but not NGF, was able to reduce the cerebrovascular deposition of AβPP seen in AD11 mice beginning at 2 months of age. Both NGF and galantamine reduced the number of Aβ-positive plaque-like deposits in the hippocampus typically observed in AD11 mice by 6 months of age.

For both compounds, the timing of therapy seems to be critical, as they are effective only when given in early stages when the pathological changes are first detectable. The authors write that they intend to try NGF and galantamine together, to see if the combination will rid the mice of all AD-like pathology.—Hakon Heimer

 

Comment by Keith Crutcher-Posted 12 September
The paper by Capsoni et al. is certainly intriguing. The potential role of NGF in AD, either in its cause or its treatment, has been difficult to pin down. Most evidence indicates that decreased levels of this neurotrophin do not explain the degeneration of basal forebrain cholinergic neurons because NGF levels are stable or even increased in AD brain. However, there is a possibility that uptake and/or utilization of NGF is impaired. If so, this animal model may well be pointing to a novel approach to dissecting the consequences of NGF deprivation and ways of countering its effects. The demonstration that pharmacological elevation of NGF (by thyroxin) or nasal administration of NGF can prevent much of the pathology makes sense insofar as NGF deprivation is the cause of the observed changes. That overlapping, but distinct, effects of galantamine were observed suggests that different pathways may be involved, as the authors note. So the neurotrophin hypothesis is by no means dead, and the results of Mark Tuszynski’s clinical trial in San Diego involving grafts of NGF-secreting fibroblasts should be quite illuminating. One remaining concern not really addressed in this study is the possibility of aberrant growth of NGF-responsive axons.—Keith Crutcher, University of Cincinnati, Ohio

Comments

  1. The AD11-transgenic mouse exhibits a progressive neurodegenerative phenotype induced by expression of anti-NGF antibodies, which resembles some key features of human Alzheimer’s disease and provides further support for the relationship between NGF and AD. In this latest paper, Capsoni et al. report on the amelioration/reversal of this neurodegenerative phenotype by intranasal administration of NGF or by peripheral injection of the nicotinic agonist/acetylcholinesterase inhibitor galantamine. Treatment appears to be time-dependent and effective only when given during the early stages of degeneration, prior to the onset of the full-blown neurodegeneration observed in aged mice.

    This data suggests that large peptides, such as NGF, can effectively circumvent the blood-brain barrier and gain access to the brain following intranasal administration. Access of intranasally administered agents to the CSF is probably limited by their molecular weight and lipophilicity. Although the rodent olfactory epithelium covers a far larger area of the nasal mucosa than in it does in humans, and diffusion distances are much shorter, this study provides support for the recent work of Born et al. 2002 who demonstrated intranasal delivery of neuropeptides to the CSF of humans.

    This paper is another interesting step forward for the use of peptides as therapeutics agents. Peptides are generally not considered a ‘sexy’ area for drug development, even though the advantages of intranasal delivery are considerable. It is rapid and bypasses the blood-brain barrier, targeting the brain directly without entry into the circulation. It thus avoids degradation by the high concentrations metabolic of enzymes in plasma and the peripheral hormone-like side effects of neuropeptides. The non-invasive nature of intranasal delivery may facilitate the treatment and prevention of many different neural disorders, in addition to AD.

    Although NGF has proved useful in this particular rodent model of sporadic AD, it is unlikely that such treatment would be beneficial in a human AD scenario either alone or in combination with a current AD therapeutic, such as galantamine. The cholinergic decline and concomitant reduction in trkA expression in the cortex and nucleus basalis of the AD brain is well documented. Hence neurotrophic factors such as NGF, which acts via trkA receptors, provide limited potential as a therapeutic strategy. Although treatment with growth factors protects against cholinergic cell death in experimental models (Haroutunian et al., 1986; Mandel et al., 1989), recent observations suggest that such neurons may simply down-regulate their phenotype, rather than die, and that treatment with such growth factors may cause a faux rescue of cholinergic neurons by re-establishing their phenotype (Haas et al., 1998, Weis et al., 2001). In support of this, Capsoni et al. have demonstrated that treatment with NGF or galantamine are effective only when given in the early stages of pathological change. Translation of this early therapeutic intervention would be practically impossible in clinical AD.

    Regardless, the AD11 mouse model provides an excellent tool for the development of therapeutic strategies targeted simultaneously at a number of markers relevant to human AD. It also provides further positive evidence that peptide drug targets may be beneficial as pharmacological agents for the treatment of both neurological and psychiatric conditions.

    References:

    Haas CA, Frotscher M. Role of NGF in axotomy-induced c-Jun expression in medial septal cholinergic neurons. Int J Dev Neurosci. 1998 Nov-Dec;16(7-8):691-703. PubMed.

    Haroutunian V, Kanof PD, Davis KL. Partial reversal of lesion-induced deficits in cortical cholinergic markers by nerve growth factor. Brain Res. 1986 Oct 29;386(1-2):397-9. PubMed.

    Mandel RJ, Gage FH, Thal LJ. Spatial learning in rats: correlation with cortical choline acetyltransferase and improvement with NGF following NBM damage. Exp Neurol. 1989 Jun;104(3):208-17. PubMed.

    Weis C, Marksteiner J, Humpel C. Nerve growth factor and glial cell line-derived neurotrophic factor restore the cholinergic neuronal phenotype in organotypic brain slices of the basal nucleus of Meynert. Neuroscience. 2001;102(1):129-38. PubMed.

    View all comments by TracyAnn Perry

  2. First detailed characterization of the Aβ immunoreactive deposits in these anti-NGF mice. A lot of questions were raised since the initial publication in PNAS a couple of years ago. In this paper, the changes are impressive but these are really not traditional Aβ deposits or amyloid plaques seen in either AD brains or in APP transgenic mice.

    View all comments by Edward Koo

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References

External Citations

  1. see Ruberti et al. 2000
  2. Capsoni et al., 2000
  3. Pesavento et al. 2002

Further Reading

Primary Papers

  1. 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.
  2. 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.

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