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

Abstract

SummaryAlzheimer's disease (AD) is a progressive neurodegenerative disorder associated with synaptic dysfunction, pathological accumulation of β‐amyloid (Aβ), and neuronal loss. The self‐association of Aβ monomers into soluble oligomers seems to be crucial for the development of neurotoxicity (J. Neurochem., 00, 2007 and 1172). Aβ oligomers have been suggested to compromise neuronal functions in AD by reducing the expression levels of the CREB target gene and brain‐derived neurotrophic factor (BDNF) (J. Neurosci., 27, 2007 and 2628; Neurobiol. Aging, 36, 2015 and 20406 Mol. Neurodegener., 6, 2011 and 60). We previously reported a broad neuroprotective activity of physiological Aβ monomers, involving the activation of type‐1 insulin‐like growth factor receptors (IGF‐IRs) (J. Neurosci., 29, 2009 and 10582, Front Cell Neurosci., 9, 2015 and 297). We now provide evidence that Aβ monomers, by activating the IGF‐IR‐stimulated PI3‐K/AKT pathway, induce the activation of CREB in neurons and sustain BDNF transcription and release.

Type 2 Diabetes Mellitus and Alzheimer’s Disease: Role of Insulin Signalling and Therapeutic Implications

“…It is known that small oligomers of Aβ contribute to the synapto-toxicity and downstream events that lead to the neurodegenerative processes in AD [ 43 , 44 ]. As part of these neurodegenerative processes, Aβ oligomers appear to have detrimental effects on insulin signalling by inhibiting auto-phosphorylation of the receptor [ 45 ] and to markedly reduce IR levels and activity at the cell surface of the dendrites of hippocampal neurons [ 46 ].…”

A promising connection between BDNF and Alzheimer’s disease

“…Hence, Aβ monomers rightfully fall into the scenario of factors, including the nerve growth factor (NGF) and the brain-derived neurotrophic factor (BDNF), able to regulate neurocognitive functions through the engagement of specific receptors and peculiar intracellular signaling(s). We previously showed that Aβ monomers have a broad neuroprotective activity mediated by the activation of the phosphatidyl-inositol-3-kinase pathway (PI3K/AKT), via the recruitment of type-1 insulin-like growth factor receptors (IGF-IRs) [ 2 ] Interestingly, as a downstream effect of PI3K/AKT activation, Aβ monomers are able to induce the activation of the cyclic AMP response element-binding protein (CREB), thus sustaining the transcription and release of the CREB-target gene, brain derived neurotrophic factor (BDNF) [ 3 ]. CREB-induced BDNF expression could be a converging point for different actors of synaptic maintenance.…”

“…These factors would include metal dyshomeostasis, lack of NGF support, loss of functional Aβ monomers, and appearance of toxic Aβ oligomers. Accordingly, as different from Aβ monomers, oligomers are not able to activate CREB and, therefore, they do not sustain BDNF transcription and release [ 3 ].…”

“…Within this scenario, as long as they last, Aβ monomers could restrain cognitive decline by maintaining not only BDNF levels [ 3 ], but also neuronal glucose homeostasis [ 6 ] In fact, by activating IGF-IRs and promoting the translocation of the Glut3 glucose transporter from the cytosol to the plasma membrane, Aβ monomers enhance glucose uptake in neurons under basal and depolarizing conditions [ 6 ].…”

Potential therapeutics of Alzheimer's diseases: New insights into the neuroprotective role of trehalose‐conjugated beta sheet breaker peptides

“…Pure cortical neurons were obtained from E15 rat embryos. Cortical cells were dissected, mechanically dissociated and maintained in Neural Q™ Basal Medium supplemented with GS21 (Globalstem, Rockville, Maryland, US) as previously described . Cortical neurons were seeded on 24‐well plates pre‐coated with 0.1 mg mL −1 poly‐ d ‐lysine and incubated at 37°C with 5% CO 2 in a humidified atmosphere.…”