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
- 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.
- 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.