Loss of Growth Inhibitory Factor in Degenerative Disease

Abstract

Alzheimer’s disease (AD) is characterized by neuronal loss and accumulation of senile plaques and neurofibrillary tangles in cortical and subcortical regions of brain. The trophic factor hypothesis by Appel has explained neuronal loss in AD brain: failure of hippocampus and cerebral cortex to supply the neurotrophic factors for basal forebrain cholinergic neurons might lead to impairment of basal forebrain neurons.1 In addition to the degenerative characteristics, however, aberrant somatodendritic sprouting has been observed in cerebral cortex2,3,4,5 and basal forebrain6 of AD patients. The trophic factor hypothesis cannot explain the aberrant sprouting responses in AD brain. We have therefore investigated why cortical neurons exhibit higher plasticity under degenerative conditions of AD. Recently, we presented that AD brain contains higher neurotrophic activities for neonatal rat cortical neurons in vitro than non-demented aged brain,7 and that the apparent increase in neurotrophic activities is due to the decrease in growth inhibitory factor (GIF); which is a 68 amino acid metallothioneinlike protein and would suppress neurotrophic activities in normal brain.8,9 Over the last few years, we have investigated whether or not a decrease in GIF is a specific phenomenon for AD, and what kind of signals lead to the decrease in GIF. We review here the evidence to answer the above question.