Synaptic Therapy in Alzheimer's Disease: A CREB-centric Approach

Abstract

Therapeutic attempts to cure Alzheimer's disease (AD) have failed, and new strategies are desperately needed. Motivated by this reality, many laboratories (including our own) have focused on synaptic dysfunction in AD because synaptic changes are highly correlated with the severity of clinical dementia. In particular, memory formation is accompanied by altered synaptic strength, and this phenomenon (and its dysfunction in AD) has been a recent focus for many laboratories. The molecule cyclic adenosine monophosphate response element-binding protein (CREB) is at a central converging point of pathways and mechanisms activated during the processes of synaptic strengthening and memory formation, as CREB phosphorylation leads to transcription of memory-associated genes. Disruption of these mechanisms in AD results in a reduction of CREB activation with accompanying memory impairment. Thus, it is likely that strategies aimed at these mechanisms will lead to future therapies for AD. In this review, we will summarize literature that investigates 5 possible therapeutic pathways for rescuing synaptic dysfunction in AD: 4 enzymatic pathways that lead to CREB phosphorylation (the cyclic adenosine monophosphate cascade, the serine/threonine kinases extracellular regulated kinases 1 and 2, the nitric oxide cascade, and the calpains), as well as histone acetyltransferases and histone deacetylases (2 enzymes that regulate the histone acetylation necessary for gene transcription).

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

“…Based on this evidence, Teich et al . (2015) have suggested a central role for CREB and associated memory‐related genes in the synaptic effects of native Aβ.…”

“…Low doses of synthetic Aβ ensemble mimic the memory enhancement effects of endogenous Aβ (Puzzo et al ., 2008), likely via the regulation of transmitter release (Morley et al ., 2010; Puzzo et al ., 2011). Here we demonstrate that Aβ monomers are specifically able to activate CREB, a converging point for mechanisms and pathways involved in memory formation (Teich et al ., 2015). By activating IGF‐IRs and the ensuing PI3K pathway, Aβ monomers regulate the expression levels of the CREB target gene, BDNF (Scheme 1), which is deeply involved in the regulation of cognitive functions (Budni et al ., 2015).…”

Neuronal Gene Targets of NF-κB and Their Dysregulation in Alzheimer's Disease

“…Further, phosphorylation of mitochondrial CREB increased after one trial of inhibitory avoidance training, suggestive of an involvement of mitochondrial CREB in activity-dependent neural changes (Bevilaqua et al, 1999). Given these data, and the finding that synaptic deficits are the strongest correlates of cognitive dysfunction in AD (Terry et al, 1991), some have argued that therapeutic approaches directed at CREB signaling pathways constitute our best chance for treating AD (Teich et al, 2015), given the diverse role of CREB in neuronal function and positive neurobehavioral ramifications of its upregulation in AD models (De Felice et al, 2007; Saura and Valero, 2011; Teich et al, 2015). …”

Bis(propyl)-cognitin Prevents β-amyloid-induced Memory Deficits as Well as Synaptic Formation and Plasticity Impairments via the Activation of PI3-K Pathway

“…Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disease characterized by severe impairment of memory and cognitive function associated with neuronal and synaptic impairments in the brain [1]. Currently, there is no effective therapeutic treatment for AD, making AD a severe threat for human health as the global elderly population increases.…”

“…Therefore, we evaluated the effects of systemic B3C administration on spatial and recognition memory in an AD animal model. Moreover, it has been demonstrated that synaptic impairments, such as the disruption of synaptic plasticity and the loss of synapses, rather than neuronal degeneration are synchronized with the impairment of cognitive function, suggesting that synaptic impairments may play a central role in the pathogenesis of AD [1,15,16]. However, the protective role and the underlying mechanisms of B3C in Aβ-oligomer-induced synaptic impairment are virtually unknown.…”