Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling

Abstract

Changes in hippocampal function seem critical for cognitive impairment in Alzheimer's disease (AD). Although there is eventual loss of synapses in both AD and animal models of AD, deficits in spatial memory and inhibition of long-term potentiation (LTP) precede morphological alterations in the models, suggesting earlier biochemical changes in the disease. In the studies reported here we demonstrate that amyloid ␤-peptide (A␤) treatment of cultured hippocampal neurons leads to the inactivation of protein kinase A (PKA) and persistence of its regulatory subunit PKAII␣. Consistent with this, CREB phosphorylation in response to glutamate is decreased, and the decrease is reversed by rolipram, a phosphodiesterase inhibitor that raises cAMP and leads to the dissociation of the PKA catalytic and regulatory subunits. It is likely that a similar mechanism underlies 〈␤ inhibition of LTP, because rolipram and forskolin, agents that enhance the cAMP-signaling pathway, can reverse this inhibition. This reversal is blocked by H89, an inhibitor of PKA. These observations suggest that 〈␤ acts directly on the pathways involved in the formation of late LTP and agents that enhance the cAMP͞PKA͞CREB-signaling pathway have potential for the treatment of AD. A lzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by mild cognitive impairment at its onset and deficits in multiple cortical functions in later stages. To date, the vast majority of its symptoms have been attributed to the loss of synapses and the death of neurons that occur in the course of the disease. The overproduction and accumulation of the amyloid ␤-peptide (A␤) and particularly its 42-aa form (A␤ 1-42 ) have been shown to play a crucial role in both of these processes in animal models of AD (1, 2). Although these phenomena can account for the late debilitating stages of the disease, the mechanisms by which A␤ causes early cognitive and behavioral changes remain a matter of conjecture. Recent studies on animal models of AD have highlighted the discrepancy between behavioral deficits and neuropathological findings. Electrophysiological studies on mice that overexpress A␤ show impairment of long-term potentiation (LTP) that does not correlate with the extent of synaptic loss, amyloid deposition, or cell death (3-5). In addition, animals without detectable accumulation of A␤ have been reported to have behavioral deficits (6, 7). While examining gene expression in nerve growth factorprimed PC12 cells that had been exposed to A␤ 1-42 for 3 h, we observed that a group of genes including CREB2 (ATF4) and ubiquitin C-terminal hydrolase, which have been implicated in the switch from early to late LTP, were regulated in a manner consistent with an 〈␤-mediated inhibition of the cAMPmediated signaling pathway for the consolidation of LTP. ʈ The details of the biochemical pathway mediating the switch from early to late LTP have been worked out in aplysia and mice (8) and depend on the activation of the transcription factor CREB by phosphorylat...

The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism

“…Increased A␤ levels may also inhibit the expression of normal levels of ␥-secretase, because A␤ negatively regulates CREdependent gene expression, and expression of the genes encoding both PS1 and the essential ␥-secretase subunit Pen-2 is CRE-dependent (51)(52)(53). In support of a role for reduced PS expression in AD pathogenesis, PSEN1 promoter polymorphisms that reduce PS1 expression have been reported as risk factors for sporadic AD (54,55).…”

“…Alternatively, loss of PS function and increased A␤ production may converge at common downstream signaling pathways that are required for synaptic plasticity and neuronal survival. For example, both PS inactivation and increased A␤ lead to reductions in synaptic NMDA receptors and CRE-dependent gene expression (4,51,52,56).…”

The APP-interacting protein FE65 is required for hippocampus-dependent learning and long-term potentiation

“…To further test whether some of the plasticity-related signaling pathways are intact in p97FE65 À/À mice, we administered rolipram to elevate cAMP signaling. Rolipram is a specific inhibitor of the type 4 phosphodiesterase (PDE4), and it enhances the activity of cAMP/ PKA/CREB and LTP (Vitolo et al 2002;Gong et al 2004). Compared with the vehicle-injected control, rolipram-injected p97FE65 À/À mice showed significant improvement in TDPA.…”

Delayed Noradrenergic Activation in the Dorsal Hippocampus Promotes the Long-Term Persistence of Extinguished Fear

“…Norepinephrine (NE) enhances extinction memory that can be blocked by a b-receptor antagonist (Berlau and McGaugh, 2006;Mueller and Cahill, 2010;Mueller et al, 2008). The main downstream signaling pathway activated by NE/b-receptor is the protein kinase A (PKA)/cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) pathway (Kandel, 2012;Seeds and Gilman, 1971;Vitolo et al, 2002;Zhang et al, 2013). Active PKA also increases the trafficking of AMPA receptor (AMPAR) subunit GluR1 to regulate fear extinction (Matsuo et al, 2008).…”