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.
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.
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.
Comments
Amylin Pharmaceuticals
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 PerryFirst 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.
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