Diminished CRE-Induced Plasticity is Linked to Memory Deficits in Familial Alzheimer’s Disease Mice

Abstract

The mechanism underlying impaired learning and memory in Alzheimer's disease is not fully elucidated. The phosphorylation of cyclic-AMP response element binding protein (pCREB) in the hippocampus is thought to be a critical initiating step in the formation of long-term memories. Here, we tested CRE-driven gene expression following learning in mice harboring the familial Alzheimer's disease-linked APPswe/PS1ΔE9 mutations using CRE-β galactosidase reporter. We show that young adult APPswe/PS1ΔE9 mice exhibit impaired recognition memory and reduced levels of pCREB, and its cofactors CREB binding protein (CBP) and p-300 following a learning task, compared to their wild type littermate counterparts. Impairments in learning-induced activation of CREB in these mice are manifested by reduced CRE-driven gene transcription. Importantly, expression of the CRE-driven immediate early gene, Egr-1 (Zif268) is decreased in the CA1 region of the hippocampus. These studies implicate defective CREB-dependent plasticity in the mechanism underlying learning and memory deficits in Alzheimer's disease.

Amyloid Beta monomers regulate cyclic adenosine monophosphate response element binding protein functions by activating type‐1 insulin‐like growth factor receptors in neuronal cells

“…The role of CREB in AD pathology has been highlighted by the observation that pCREB is decreased in the nuclear fraction of postmortem prefrontal cortex (PFC) of individuals with AD, as compared to age‐matched, cognitively normal controls (Bartolotti et al ., 2016a,b). In the same study, the authors reported that pCREB expression in peripheral blood mononuclear cells paralleled pCREB expression in the PFC, proposing pCREB as a biomarker for cognitive function in AD.…”

“…Whether or not Aβ monomers can oppose to this process, by sustaining IGF‐1 signaling, remains to be determined. Present data suggest that, at least, monomers and oligomers exert distinct effects on CREB protein functions, and that a loss of functional monomers and a building‐up of toxic oligomers could operate coordinately in determining the CREB dysregulation observed in AD (Pugazhenthi et al ., 2011; Bartolotti et al ., 2016a,b). …”

“…This effect was not shared by pathogenic Aβ oligomers. Accordingly, CREB activation is impaired in the brain of patients with AD and Tg2576 mice (Pugazhenthi et al ., 2011; Bartolotti et al ., 2016a,b), where it is associated with decreased levels of CREB‐regulated BDNF release (Pugazhenthi et al ., 2011). Contrary to what takes place in the disease, we found that CREB activation induced by Aβ monomers was paralleled by an increased neuronal BDNF release.…”

Cognitive dysfunction in major depression and Alzheimer's disease is associated with hippocampus–prefrontal cortex dysconnectivity

“…CREB is activated by phosphorylation and drives the expression of different target genes based on the brain region where it is activated 115. It is interesting to note that CREB is also emerging as an important molecule in AD research 116,117. Postmortem studies on AD brain tissue have reported down-regulation of CREB in the hippocampus 118.…”

Preventing Jacob-induced transcriptional inactivation of CREB protects synapses from β-amyloid in Alzheimer’s Disease

“…Loss of CREB dependent gene expression after extrasynaptic NMDAR activation is a major event preceding cell death and neurodegeneration (2,(17)(18)(19)(20). Especially in AD, dysregulation of CREB dependent gene expression apparently plays a role in the onset of the disease and early synaptic dysfunction (18,19,(21)(22)(23)(24)(25)(26). The underlying mechanisms, as well as their relevance or contribution to Aβ-mediated CREB shut-off and neurodegeneration in AD, are still unknown (18,19).…”