Synaptic loss in cognitively impaired aged rats is ameliorated by chronic human nerve growth factor infusion

In the present study, we assessed the synaptic changes in aged impaired and unimpaired rats, and the effect of exogenous human nerve growth factor administration on behavioral activity and synaptic density. Human nerve growth factor was administered into the rat ventricles with a cannula connected to an osmotic pump in adult, aged impaired and unimpaired rats. Behavioral performance was evaluated in the Morris water maze. Aged impaired rats had an 18 +/- 4% decrease in the number of synaptophysinimmunoreactive presynaptic terminals as compared to aged unimpaired rats. After a continuous four-week human nerve growth factor, the aged impaired rats displayed a significant 16 +/- 3% increase in the number of synaptophysin-immunoreactive presynaptic terminals in the frontal cortex, as compared to aged impaired rats treated with vehicle. This increase correlated with an improvement in water maze performance (r = -0.74, P < 0.001). Measurements of synaptophysin-immunoreactive presynaptic terminals in other cortical and subcortical regions did not show any statistically significant difference or correlations among the various groups. These results support the possibility that nerve growth factor mediates the induction of other trophic factors which, in turn, might potentially produce a sprouting response of non-cholinergic fibers that ameliorate the cognitive deficits in impaired, aged rats.

[1]  F. Gage,et al.  Nerve Growth Factor Expression and Function in the CNS , 1991 .

[2]  P. Greengard,et al.  A 38,000-dalton membrane protein (p38) present in synaptic vesicles. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[3]  B Carragher,et al.  Three-Dimensional Analysis of the Relationship Between Synaptic Pathology and Neuropil Threads in Alzheimer Disease , 1992, Journal of neuropathology and experimental neurology.

[4]  G. Buzsáki,et al.  NGF-dependent sprouting and regeneration in the hippocampus. , 1990, Progress in brain research.

[5]  F. Gage,et al.  Morphological response of axotomized septal neurons to nerve growth factor , 1988, The Journal of comparative neurology.

[6]  M. Igarashi,et al.  Decreased synaptic density in aged brains and its prevention by rearing under enriched environment as revealed by synaptophysin contents , 1994, Journal of neuroscience research.

[7]  F. Gage,et al.  Altered levels of amyloid protein precursor transcripts in the basal forebrain of behaviorally impaired aged rats. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[8]  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.

[9]  C. Masters,et al.  The amyloid protein precursor of Alzheimer's disease is a mediator of the effects of nerve growth factor on neurite outgrowth , 1992, Neuron.

[10]  A. Cuello,et al.  Nerve growth factor-induced synaptogenesis and hypertrophy of cortical cholinergic terminals. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

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

[12]  F. Gage,et al.  Continuous infusion of nerve growth factor prevents basal forebrain neuronal death after fimbria fornix transection. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[13]  N. Sims,et al.  [14C]acetylcholine synthesis and [14C]carbon dioxide production from [U-14C]glucose by tissue prisms from human neocortex. , 1981, The Biochemical journal.

[14]  Bertram Wiedenmann,et al.  Identification and localization of synaptophysin, an integral membrane glycoprotein of Mr 38,000 characteristic of presynaptic vesicles , 1985, Cell.

[15]  L. Thal,et al.  Independent effects of age and nucleus basalis magnocellularis lesion: maze learning, cortical neurochemistry, and morphometry. , 1992, Behavioral neuroscience.

[16]  E. Masliah,et al.  Quantitative synaptic alterations in the human neocortex during normal aging , 1993, Neurology.

[17]  E. Masliah,et al.  Spectrum of human immunodeficiency virus–associated neocortical damage , 1992, Annals of neurology.

[18]  E. Arenas,et al.  Involvement of Nerve Growth Factor and Its Receptor in the Regulation of the Cholinergic Function in Aged Rats , 1991, Journal of neurochemistry.

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

[20]  B. Costello,et al.  Factors influencing GAP-43 gene expression in PC12 pheochromocytoma cells , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[21]  Fred H. Gage,et al.  Reactive synaptogenesis assessed by synaptophysin immunoreactivity is associated with GAP-43 in the dentate gyrus of the adult rat , 1991, Experimental Neurology.

[22]  H. C. Moises,et al.  Exogenous NGF Affects Cholinergic Transmitter Function and Y-Maze Behavior in Aged Fischer 344 Male Rats , 1991, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[23]  N. Robakis,et al.  Effects of Neurotrophic Factors on the Secretion and Metabolism of the Alzheimer Amyloid Precursor , 1991 .

[24]  P. Greengard,et al.  Quantitation of nerve terminal populations: Synaptic vesicle‐associated proteins as markers for synaptic density in the rat neostriatum , 1988, Synapse.

[25]  H. Federoff,et al.  Dual regulation of GAP-43 gene expression by nerve growth factor and glucocorticoids. , 1988, The Journal of biological chemistry.

[26]  D. Salmon,et al.  Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairment , 1991, Annals of neurology.

[27]  S. Shimohama,et al.  Trophic effect of beta-amyloid precursor protein on cerebral cortical neurons in culture. , 1991, Biochemical and biophysical research communications.

[28]  R. Katzman.,et al.  Alzheimer's disease is a degenerative disorder , 1989, Neurobiology of Aging.

[29]  D. G. Jones.  Current topics in research on synapses , 1984 .

[30]  F. Hefti,et al.  Growth Factors and Alzheimer’s Disease , 1991, Research and Perspectives in Alzheimer’s Disease.

[31]  R. Mervis,et al.  Exogenous Nerve Growth Factor Reverses Age‐Related Structural Changes in Neocortical Neurons in the Aging Rat , 1991, Annals of the New York Academy of Sciences.

[32]  Dallas E. Johnson,et al.  Analysis of messy data , 1992 .

[33]  F. Hefti,et al.  Function of neurotrophic factors in the adult and aging brain and their possible use in the treatment of neurodegenerative diseases , 1989, Neurobiology of Aging.

[34]  V. Luine,et al.  Spatial memory deficits in aged rats: contributions of the cholinergic system assessed by ChAT , 1990, Brain Research.

[35]  D. Kirschner,et al.  Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. , 1990, Science.

[36]  B. Spruijt,et al.  Quantitation of the growth‐associated protein B‐50/GAP‐43 and neurite outgrowth in PC12 cells , 1991, Journal of neuroscience research.

[37]  A. R. Brooks,et al.  Neonatal lesions of the basal forebrain cholinergic neurons result in abnormal cortical development. , 1988, Brain research.

[38]  F. Gage,et al.  NGF receptor reexpression and NGF-mediated cholinergic neuronal hypertrophy in the damaged adult neostriatum , 1989, Neuron.

[39]  B. Will,et al.  Nerve Growth Factor and Behavioral Recovery After Brain Damage in Rats , 1991 .