Systemic Administration of a Nerve Growth Factor Conjugate Reverses Age-Related Cognitive Dysfunction and Prevents Cholinergic Neuron Atrophy

Intraventricular administration of nerve growth factor (NGF) in rats has been shown to reduce age-related atrophy of central cholinergic neurons and the accompanying memory impairment. Intraventricular administration of NGF is necessary because NGF will not cross the blood–brain barrier (BBB). Here we have used a novel carrier system, consisting of NGF covalently linked to an anti-transferrin receptor antibody (OX-26), to transport biologically active NGF across the BBB. In our experiment, aged (24 months old) Fischer 344 rats received intravenous injections of the OX-26-NGF conjugate or a control solution (a mixture of unconjugated OX-26 and NGF) twice weekly for 6 weeks. The OX-26-NGF injections resulted in a significant improvement in spatial learning in previously impaired rats but disrupted the learning ability of previously unimpaired rats. Neuroanatomical analyses showed that OX-26-NGF conjugate treatment resulted in a significant increase in cholinergic cell size in the medial septal region of rats initially impaired in spatial learning. These results indicate the potential use of the transferrin receptor antibody delivery system for treatment of CNS disorders with neurotrophic proteins.

[1]  G. Taglialatela,et al.  Regional CNS uptake of blood‐borne nerve growth factor , 1994, Journal of neuroscience research.

[2]  R. Loy,et al.  Age-related loss of nerve growth factor sensitivity in rat basal forebrain neurons , 1988, Brain Research.

[3]  F. Gage,et al.  NGF improves spatial memory in aged rodents as a function of age , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[4]  D. Olton,et al.  Variable-interval probe test as a tool for repeated measurements of spatial memory in the water maze. , 1993, Behavioral neuroscience.

[5]  M. Johnston,et al.  Choline acetyltransferase activity in striatum of neonatal rats increased by nerve growth factor. , 1985, Science.

[6]  L. Williams,et al.  Exogenous nerve growth factor stimulates choline acetyltransferase activity in aging Fischer 344 male rats , 1991, Neurobiology of Aging.

[7]  F. Bloom,et al.  NGF and anti-transferrin receptor antibody conjugate: short and long-term effects on survival of cholinergic neurons in intraocular septal transplants. , 1994, The Journal of pharmacology and experimental therapeutics.

[8]  F. Gage,et al.  Nerve growth factor receptor and choline acetyltransferase colocalization in neurons within the rat forebrain: Response to fimbria‐fornix transection , 1989, The Journal of comparative neurology.

[9]  H. Thoenen,et al.  Nerve growth factor (NGF) in the rat CNS: Absence of specific retrograde axonal transport and tyrosine hydroxylase induction in locus coeruleus and substantia nigra , 1979, Brain Research.

[10]  M. Schwab,et al.  NGF-mediated increase of choline acetyltransferase (ChAT) in the neonatal rat forebrain: evidence for a physiological role of NGF in the brain? , 1983, Brain research.

[11]  G. Buzsáki,et al.  Morphologic alterations of choline acetyltransferase-positive neurons in the basal forebrain of aged behaviorally characterized fisher 344 rats , 1993, Neurobiology of Aging.

[12]  F. Hefti,et al.  Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[13]  A. Granholm,et al.  Delivery of Trophic Factors to the Primate Brain , 1993, Experimental Neurology.

[14]  D. Olton,et al.  Human nerve growth factor improves spatial memory in aged but not in young rats , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[15]  H. Thoenen,et al.  Neurotrophic factors. , 1985, Science.

[16]  K. Crutcher,et al.  NGF-induced remodeling of mature uninjured axon collaterals , 1990, Brain Research.

[17]  F. Gage,et al.  Progressive decline in spatial learning and integrity of forebrain cholinergic neurons in rats during aging , 1992, Neurobiology of Aging.

[18]  I. Strömberg,et al.  Effects of transferrin receptor antibody—NGF conjugate on young and aged septal transplants in oculo , 1995, Experimental Neurology.

[19]  H. Markram,et al.  Regional changes in ngf receptor immunohistochemical labeling in the septum of the aged rat , 1990, Neurobiology of Aging.

[20]  R. Bartus,et al.  The cholinergic hypothesis of geriatric memory dysfunction. , 1982, Science.

[21]  A. Björklund,et al.  Reversal of spatial memory impairments in aged rats by nerve growth factor and neurotrophins 3 and 4/5 but not by brain-derived neurotrophic factor. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[22]  C. Scali,et al.  Nerve growth factor increases extracellular acetylcholine levels in the parietal cortex and hippocampus of aged rats and restores object recognition , 1994, Neuroscience Letters.

[23]  F. Gage,et al.  Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor , 1987, Nature.

[24]  M. Barbacid,et al.  High-affinity nerve growth factor receptor (Trk) immunoreactivity is localized in cholinergic neurons of the basal forebrain and striatum in the adult rat brain , 1993, Brain Research.

[25]  M. Schwab,et al.  Specific retrograde transport of nerve growth factor (NGF) from neocortex to nucleus basalis in the rat , 1984, Brain Research.

[26]  B. Winblad,et al.  Nerve growth factor affects11C-nicotine binding, blood flow, EEG, and verbal episodic memory in an Alzheimer patient (Case Report) , 1992 .

[27]  L. Mendell,et al.  Nerve growth factor and nociception , 1993, Trends in Neurosciences.

[28]  M. Abercrombie.  Estimation of nuclear population from microtome sections , 1946, The Anatomical record.

[29]  L. Mendell,et al.  Peripheral and Central Mechanisms of NGF‐induced Hyperalgesia , 1994, The European journal of neuroscience.

[30]  F. Gage,et al.  Somatic gene transfer of NGF to the aged brain: behavioral and morphological amelioration , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[31]  F. Hefti,et al.  Comparison of nerve growth factor's effects on development of septum, striatum, and nucleus basalis cholinergic neurons in vitro , 1988, Journal of neuroscience research.

[32]  L. F. Kromer.  Nerve growth factor treatment after brain injury prevents neuronal death. , 1987, Science.

[33]  W. Jefferies,et al.  Transferrin receptor on endothelium of brain capillaries , 1984, Nature.

[34]  A. Granholm,et al.  Glial cell line‐derived neurotrophic factor supports survival of injured midbrain dopaminergic neurons , 1995, The Journal of comparative neurology.

[35]  Variable-interval probe test as a tool for repeated measurements of spatial memory in the water maze. , 1993, Behavioral neuroscience.

[36]  F. Bloom,et al.  Blood-brain barrier penetration and in vivo activity of an NGF conjugate. , 1993, Science.

[37]  P. Aisen,et al.  Iron transport and storage proteins. , 1980, Annual review of biochemistry.

[38]  T. Collier,et al.  Loss of NGF receptor immunoreactivity in basal forebrain neurons of aged rats: correlation with spatial memory impairment , 1989, Brain Research.

[39]  C. Flexner,et al.  The effect of systemically administered recombinant human nerve growth factor in healthy human subjects , 1994, Annals of neurology.