Age-dependent loss of NGF signaling in the rat basal forebrain is due to disrupted MAPK activation.
The loss of nerve growth factor (NGF) and its high affinity receptor TrkA has been implicated in the loss of cholinergic tone and function in Alzheimer's disease (AD) and normal aging. We employed an animal model of aging, the aged rat, which also exhibits memory loss and NGF alterations. Basal forebrain TrkA levels increased after injection of NGF in the hippocampus within 1h in young rats, but this response was diminished in aged animals as determined by Western blot analysis. Further, NGF activated MAPK pathways without changing total ERK levels and the activation of these pathways was also diminished in aged animals. The exogenous NGF injection did not appear to activate the PI-3K pathway or alter total levels of Akt significantly. These data shed light on mechanisms of NGF signaling in the CNS, and alterations in this signaling cascade associated with age and memory loss. These findings might lead to development of novel treatment therapies for the memory loss associated with AD and other age-associated neurodegenerative diseases.
Williams
Brice
B
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA.
Granholm
Ann-Charlotte
AC
Sambamurti
Kumar
K
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport / Q000502:physiology; D020532:Basal Nucleus of Meynert / Q000378:metabolism* / Q000503:physiopathology; D002799:Cholinergic Fibers / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008569:Memory Disorders / Q000378:metabolism / Q000503:physiopathology; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D009434:Neural Pathways / Q000378:metabolism* / Q000503:physiopathology; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020917:Receptor, trkA / Q000378:metabolism
D020932:Nerve Growth Factor; D020917:Receptor, trkA; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases