Age-dependent differential regulation of genes encoding APP and alpha-synuclein in hippocampal synaptic plasticity.

Abstract

We investigated the modulation of the messenger RNA encoding the amyloid precursor protein (APP) and alpha-synuclein following induction of long-term potentiation (LTP) in the dentate gyrus of young and aged rats. Three hours after tetanic stimulation, LTP induced in the young rats was maintained; the aged rats, however, fell into two subgroups: those in which LTP was maintained, and those in which LTP had declined to basal levels. In young rats, the global expression of mRNAs of all isoforms of APP and in particular that of the isoform lacking the KPI domain were significantly upregulated. In aged rats, the global expression of mRNAs of all isoforms of APP was not modified, regardless of whether LTP was maintained or not. The level of mRNA encoding the Kunitz protease-inhibitory (KPI)-minus isoform of APP, however, was increased in aged rats in which LTP was maintained, suggesting that the gene of this isoform may be more specifically regulated by synaptic plasticity. In contrast, we found that the gene encoding alpha-synuclein showed a trend towards being downregulated at the mRNA level in young rats following LTP, and significantly so in aged rats in which LTP was maintained, whereas it was not downregulated in aged rats with decremental LTP. These data suggest that the regulated expression of APP isoforms is part of the tanscriptional response associated with the enduring forms of synaptic plasticity and is altered with age. Whereas the level of alpha-synuclein mRNA is not apparently modified in normal LTP, it may reflect a mechanism of apoptotic cell death in aging that is in part responsible for decremental synaptic plasticity.