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

Abstract

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.

The PDE4 Inhibitor HT-0712 Improves Hippocampus-Dependent Memory in Aged Mice

“…In aged memory-impaired rats, hippocampal levels of CREB1 protein were found to be reduced when compared with young rats (Brightwell et al, 2004). Experience-dependent activation of CREB and its downstream targets is altered in aged mice (Porte et al, 2008) and rats (Monti et al, 2005;Countryman and Gold, 2007). Further, hippocampal mRNA expression of the adenyl cyclases AC1 and AC9 (Mons et al, 2004) and activation of protein kinase A (Karege et al, 2001) are reduced in the hippocampus of aged rodents.…”

“…For example, age-impaired rats have reduced levels of CREB protein in hippocampus, whereas such CREB levels are normal in age-unimpaired or young rats (Brightwell et al, 2004). Activation of CREB by Ser133 phosphorylation and expression of the CREBregulated gene, C/EBPb, in hippocampus are reduced after context conditioning in aged rats (Monti et al, 2005). Importantly, overexpression of CREB in hippocampus attenuates memory deficits in aged rats (Mouravlev et al, 2006).…”

The endocannabinoid system in normal and pathological brain ageing

“…Generally, decreased CREB activity was associated with learning impairments in healthy aged animals [31,32] and with cognitive deficits in animal models of neurodegenerative disorders [33][34][35]. Importantly, the level of phosphorylated CREB and the activity-induced increase in CREB phosphorylation is diminished in ageing [36,37], and this itself may influence the ageing process [38,39]. Altered calcium signalling in ageing neurons significantly contributes to diminished CREB activity.…”

Ebbinghaus Revisited: Influences of the BDNF Val66Met Polymorphism on Backward Serial Recall Are Modulated by Human Aging

“…Aging is associated with reduced brain resources at multiple levels, including changes in gray and white matter integrity as well as losses in neuromodulatory functions (see Bäckman, Nyberg, Lindenberger, Li, & Farde, 2006;Cabeza, Nyberg, & Park, 2005;Raz et al, 2005;Li, Lindenberger & Sikström, 2001 for reviews). Of particular relevance to the current research, both animal and human evidence shows that activity-dependent up-regulation of BDNF and the level of its receptor tyrosine kinase B (trkB) are compromised in old age (Webster, Herman, Kleinman, & Shannon Weickert, 2006;Adlard, Perreau, & Cotman, 2005;Monti, Berteotti, & Contestabile, 2005; see TapiaArancibia, Rage, Givalois, & Arancibia, 2004, for a review). Lindenberger et al (2008) hypothesized that age-related losses in structural and neurochemical brain resources may modulate the extent to which common genetic variations affect cognitive functioning.…”