Cyclic AMP Enhancers and Aβ Oligomerization Blockers as Potential Therapeutic Agents in Alzheimers Disease

Felice, Fernanda G. De; Wasilewska-Sampaio, Ana Paula; Barbosa, Anna Carolina A P; Gomes, Flávia Carvalho Alcântara; Klein, William L.; Ferreira, Sérgio T.

doi:10.2174/156720507781077287

Cited by 41 publications

(7 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also found that EGCG treatment increased the phosphorylation of CREB by activating NGF/TrkA signaling, in accord with the results of Autio et al [44] that acetylcholinesterase inhibitors donepezil and galantamine increased the phosphorylation of TrkA and CREB. The activation and phosphorylation of CREB also inhibit the Aβ oligomerization and formation and decrease the Aβ neurotoxicity [45, 46]. In addition, CREB activation also reduced the messenger RNA and protein expression of γ-secretase in APP processing [47], which in turn attenuated the formation of Aβ.…”

Section: Discussionmentioning

confidence: 99%

(−)-Epigallocatechin-3-Gallate Ameliorates Learning and Memory Deficits by Adjusting the Balance of TrkA/p75NTR Signaling in APP/PS1 Transgenic Mice

et al. 2013

View full text Add to dashboard Cite

Alzheimer's disease (AD) is pathologically characterized by deposition of β-amyloid (Aβ) peptides, which closely correlates with the balance of nerve growth factor (NGF)-related TrkA/p75NTR signaling. (−)-Epigallocatechin-3-gallate (EGCG) is used for prevention and treatment of many neurodegenerative diseases, including AD. However, whether the neuroprotective effects of EGCG treatment were via modulating the balance of TrkA/p75NTR signaling was still unknown. In this study, we found that EGCG treatment (2 mg · kg –1 · day –1) dramatically ameliorated the cognitive impairments, reduced the overexpressions of Aβ(1–40) and amyloid precursor protein (APP), and inhibited the neuronal apoptosis in the APP/PS1 mice. Interestingly, the EGCG treatment enhanced the relative expression level of NGF by increasing the NGF/proNGF ratio in the APP/PS1 mice. Moreover, after EGCG treatment, TrkA signaling was activated by increasing the phosphorylation of TrkA following the increased phosphorylation of c-Raf, ERK1/2, and cAMP response element-binding protein (CREB), simultaneously the p75NTR signaling was significantly inhibited by decreasing the p75ICD expression, JNK2 phosphorylation, and cleaved-caspase 3 expression, so that the Aβ deposits and neuronal apoptosis in the hippocampus were inhibited.

show abstract

Section: Discussionmentioning

confidence: 99%

(−)-Epigallocatechin-3-Gallate Ameliorates Learning and Memory Deficits by Adjusting the Balance of TrkA/p75NTR Signaling in APP/PS1 Transgenic Mice

et al. 2013

View full text Add to dashboard Cite

show abstract

“…This scaffolding effect can be construed as analogous to formation of focal contacts, but with pathogenic consequences when AβOs become attached. Not only Ca 2+ but cAMP levels [24, 156] could be disrupted. It is intriguing that once neurons have reached a fully differentiated state, PrP can enzymatically be removed with little or no impact on AβO accumulation in hot spots and synapses [180].…”

Section: Transduction Mechanismmentioning

confidence: 99%

Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis

2015

View full text Add to dashboard Cite

Protein aggregation is common to dozens of diseases including prionoses, diabetes, Parkinson’s and Alzheimer’s. Over the past 15 years, there has been a paradigm shift in understanding the structural basis for these proteinopathies. Precedent for this shift has come from investigation of soluble Aβ oligomers (AβOs), toxins now widely regarded as instigating neuron damage leading to Alzheimer’s dementia. Toxic AβOs accumulate in AD brain and constitute long-lived alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. Key experiments using fibril-free AβO solutions demonstrated that while Aβ is essential for memory loss, the fibrillar Aβ in amyloid deposits is not the agent. The AD-like cellular pathologies induced by AβOs suggest their impact provides a unifying mechanism for AD pathogenesis, explaining why early stage disease is specific for memory and accounting for major facets of AD neuropathology. Alternative ideas for triggering mechanisms are being actively investigated. Some research favors insertion of AβOs into membrane, while other evidence supports ligand-like accumulation at particular synapses. Over a dozen candidate toxin receptors have been proposed. AβO binding triggers a redistribution of critical synaptic proteins and induces hyperactivity in metabotropic and ionotropic glutamate receptors. This leads to Ca2+ overload and instigates major facets of AD neuropathology, including tau hyperphosphorylation, insulin resistance, oxidative stress, and synapse loss. Because different species of AβOs have been identified, a remaining question is which oligomer is the major pathogenic culprit. The possibility has been raised that more than one species plays a role. Despite some key unknowns, the clinical relevance of AβOs has been established, and new studies are beginning to point to co-morbidities such as diabetes and hypercholesterolemia as etiological factors. Because pathogenic AβOs appear early in the disease, they offer appealing targets for therapeutics and diagnostics. Promising therapeutic strategies include use of CNS insulin signaling enhancers to protect against the presence of toxins and elimination of the toxins through use of highly specific AβO antibodies. An AD-dependent accumulation of AβOs in CSF suggests their potential use as biomarkers and new AβO probes are opening the door to brain imaging. Overall, current evidence indicates that Aβ oligomers provide a substantive molecular basis for the cause, treatment and diagnosis of Alzheimer’s disease.

show abstract

“…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). …”

Section: Creb In Admentioning

confidence: 99%

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

Snow

Albensi

2016

Front. Mol. Neurosci.

118

View full text Add to dashboard Cite

Although, better known for its role in inflammation, the transcription factor nuclear factor kappa B (NF-κB) has more recently been implicated in synaptic plasticity, learning, and memory. This has been, in part, to the discovery of its localization not just in glia, cells that are integral to mediating the inflammatory process in the brain, but also neurons. Several effectors of neuronal NF-κB have been identified, including calcium, inflammatory cytokines (i.e., tumor necrosis factor alpha), and the induction of experimental paradigms thought to reflect learning and memory at the cellular level (i.e., long-term potentiation). NF-κB is also activated after learning and memory formation in vivo. In turn, activation of NF-κB can elicit either suppression or activation of other genes. Studies are only beginning to elucidate the multitude of neuronal gene targets of NF-κB in the normal brain, but research to date has confirmed targets involved in a wide array of cellular processes, including cell signaling and growth, neurotransmission, redox signaling, and gene regulation. Further, several lines of research confirm dysregulation of NF-κB in Alzheimer's disease (AD), a disorder characterized clinically by a profound deficit in the ability to form new memories. AD-related neuropathology includes the characteristic amyloid beta plaque formation and neurofibrillary tangles. Although, such neuropathological findings have been hypothesized to contribute to memory deficits in AD, research has identified perturbations at the cellular and synaptic level that occur even prior to more gross pathologies, including transcriptional dysregulation. Indeed, synaptic disturbances appear to be a significant correlate of cognitive deficits in AD. Given the more recently identified role for NF-κB in memory and synaptic transmission in the normal brain, the expansive network of gene targets of NF-κB, and its dysregulation in AD, a thorough understanding of NF-κB-related signaling in AD is warranted and may have important implications for uncovering treatments for the disease. This review aims to provide a comprehensive view of our current understanding of the gene targets of this transcription factor in neurons in the intact brain and provide an overview of studies investigating NF-κB signaling, including its downstream targets, in the AD brain as a means of uncovering the basic physiological mechanisms by which memory becomes fragile in the disease.

show abstract

Cyclic AMP Enhancers and Aβ Oligomerization Blockers as Potential Therapeutic Agents in Alzheimers Disease

Cited by 41 publications

References 58 publications

(−)-Epigallocatechin-3-Gallate Ameliorates Learning and Memory Deficits by Adjusting the Balance of TrkA/p75NTR Signaling in APP/PS1 Transgenic Mice

(−)-Epigallocatechin-3-Gallate Ameliorates Learning and Memory Deficits by Adjusting the Balance of TrkA/p75NTR Signaling in APP/PS1 Transgenic Mice

Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis

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

Contact Info

Product

Resources

About