Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF)

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• 作者：Sumangali Kailainathan^a ; ^e ; ¹ ; Thomas M. Piers^a ; ^b ; ^c ; ¹ ; Jee Hyun Yi^a ; ^b ; Seongmin Choi^a ; ^b ; ^c ; Mark S. Fahey^a ; Eva Borger^d ; Frank J. Gunn-Moore^d ; Laurie O&rsquo ; Neill^a ; ^b ; Michael Lever^a ; ^b ; Daniel J. Whitcomb^a ; ^b ; ^c ; Kwangwook Cho^a ; ^b ; ^c ; ¹ ; ^{Kei.Cho@bristol.ac.uk" class="auth_mail" title="E-mail the corresponding author} ; Shelley J. Allen^a ; ^e ; ¹ ; ^{shelley.allen@bristol.ac.uk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：JC-1 dye ; 5&prime ; 6 ; 6&prime ; -tetrachloro-1 ; 1&prime ; 3 ; 3&prime ; -tetraethylbenzimidazolylcarbocyanine iodide ; AD ; Alzheimer&rsquo ; s disease ; ANOVA ; analysis of variance ; aCSF ; artificial cerebrospinal fluid ; BDNF ; brain-derived neurotrophic factor ; CD ; circular dichroism ; DIV ; days in vitro ; DTT ; dithiothreitol ; ECD ; extracellular domain ; fEPSP ; field excitatory postsynaptic potentials ; FCR ; furin cleavage-resistant ; GSK3β ; glycogen synthase kinase 3β ; IPTG ; isopropyl β-D-1-thiogalactopyranoside
• 刊名：Pharmacological Research
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：104
• 期：Complete
• 页码：97-107
• 全文大小：2377 K

文摘

This study describes a fundamental functional difference between the two main polymorphisms of the pro-form of brain-derived neurotrophic factor (proBDNF), providing an explanation as to why these forms have such different age-related neurological outcomes. Healthy young carriers of the Met66 form (present in ∼30% Caucasians) have reduced hippocampal volume and impaired hippocampal-dependent memory function, yet the same polymorphic population shows enhanced cognitive recovery after traumatic brain injury, delayed cognitive dysfunction during aging, and lower risk of late-onset Alzheimer’s disease (AD) compared to those with the more common Val66 polymorphism. To examine the differences between the protein polymorphisms in structure, kinetics of binding to proBDNF receptors and in vitro function, we generated purified cleavage-resistant human variants. Intriguingly, we found no statistical differences in those characteristics. As anticipated, exogenous application of proBDNF Val66 to rat hippocampal slices dysregulated synaptic plasticity, inhibiting long-term potentiation (LTP) and facilitating long-term depression (LTD). We subsequently observed that this occurred via the glycogen synthase kinase 3β (GSK3β) activation pathway. However, surprisingly, we found that Met66 had no such effects on either LTP or LTD. These novel findings suggest that, unlike Val66, the Met66 variant does not facilitate synapse weakening signaling, perhaps accounting for its protective effects with aging.