Dysregulation of memory-related proteins in the hippocampus of aged rats and their relation with cognitive impairment.

In the present experiments, we used conditioned fear to study whether changes in expression or functional state of proteins known to be involved in hippocampal learning could suggest correlation with age-related memory deficits. We focused on both alterations constitutively present in the hippocampus of aged rats and alterations related to different learning responses. Our results point at the dysregulation of the phosphorylation state of CREB in the hippocampus of aged rats as a primary biochemical correlate of their impaired memory. Other proteins, known to be important for various steps of memory formation and consolidation and linked to CREB, are to some extent altered in their constitutive expression or in the response to learning in the aged hippocampus. In particular, phosphorylated CREB and Arc, a protein functionally related to CREB in memory consolidation, are both present at constitutively higher levels in the hippocampus of aged rats, but they are not susceptible to the learning-related up-regulation occurring in young adults. Two other CREB-regulated proteins involved in memory consolidation, the neurotrophin BDNF and the transcription factor C/EBPbeta, are expressed at similar levels in the hippocampus of young-adult and aged rats, but their response to conditioned fear learning appears dysregulated by aging. Calcineurin, a protein phosphatase having CREB among its substrates and whose expression negatively correlates with learning, is more expressed in the hippocampus of aged rats. However, while calcineurin expression decreases in the hippocampus of young adults after learning, no changes are observed in the hippocampus of aged, learning-impaired rats. (c) 2005 Wiley-Liss, Inc.