Reduced pCREB in Alzheimer’s disease prefrontal cortex is reflected in peripheral blood mononuclear cells

Abstract

Cyclic-AMP response element-binding protein (CREB) signaling has a critical role in the formation of memories. CREB signaling is dysfunctional in the brains of mouse models of Alzheimer's disease (AD), and evidence suggests that CREB signaling may be disrupted in human AD brains as well. Here, we show that both CREB and its activated form pCREB-Ser133 (pCREB) are reduced in the prefrontal cortex of AD patients. Similarly, the transcription cofactors CREB-binding protein (CBP) and p300 are reduced in the prefrontal cortex of AD patients, indicating additional dysfunction of CREB signaling in AD. Importantly, we show that pCREB expression is reduced in peripheral blood mononuclear cells (PBMC) of AD subjects. In addition, pCREB levels in PBMC positively correlated with pCREB expression in the postmortem brain of persons with AD. These results suggest that pCREB expression in PBMC may be indicative of its expression in the brain, and thus offers the intriguing possibility of pCREB as a biomarker of cognitive function and disease progression in AD.

The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non‐human primate model of Alzheimer's disease

“…These findings are consistent with some reports showing decreased PKA activity in AD brain . On the other hand, a recent study did not observe decreases in PKA levels in the prefrontal cortex of AD patients . In addition, a very recent study showed that insulin deficiency induces the activity of PKA and results in tau phosphorylation .…”

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.…”

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

“…Interestingly, the improvement in spatial memory occurred independently of amyloid-β plaque load and might be related to the extent of synapse loss, which is a more robust correlate of cognitive impairment in AD patients at an early stage than amyloid-β or neurofibrillary tangle pathology (56,(77)(78)(79). Thus, measures to enhance CREB activity might restore learning and memory through compensatory mechanisms that circumvent amyloid-β pathology.…”