Dendritic and axonal mechanisms of Ca<sup>2+</sup> elevation impair BDNF transport in Aβ oligomer–treated hippocampal neurons

Gan, Kathlyn J.; Silverman, Michael

doi:10.1091/mbc.e14-12-1612

Cited by 32 publications

(17 citation statements)

References 74 publications

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“…A simplified scheme illustrating some of the mechanisms by which AβOs (AβOs; represented as red asterisks) impact synapse plasticity and function. At the pre-synaptic terminal, AβOs inhibit microtubule-based fast axonal transport (FAT) in a tau-independent manner (Decker et al, 2010b ; Ramser et al, 2013 ; Gan and Silverman, 2015 ; Takach et al, 2015 ), resulting in reduced or interrupted transport of various cargoes, including brain-derived neurotrophic factor (BDNF), to synapses. FAT inhibition may involve physical or functional interaction of AβOs with axonal voltage-gated calcium channels (VGCC), calcium influx into the axon and activation of calcineurin (CaN).…”

Section: Discussionmentioning

confidence: 99%

“…Many studies have provided evidence (largely from immunofluorescence co-localization and/or co-immunoprecipitation experiments) supporting the notion that AβOs bind to excitatory synapses. However, recent studies have provided evidence that oligomers also bind to axons, albeit less robustly than to dendrites (Baleriola et al, 2014 ; Gan and Silverman, 2015 ), and that axonal binding may be, at least in part, responsible for the inhibition of fast axonal transport induced by AβOs (Decker et al, 2010b ; Bomfim et al, 2012 ; Ramser et al, 2013 ). The specificity of synaptic targeting by AβOs thus deserves further examination.…”

Section: Aβos As Synaptotoxins In Admentioning

confidence: 99%

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Soluble amyloid-Î² oligomers as synaptotoxins leading to cognitive impairment in Alzheimerâ€™s disease

Ferreira

Lourenco

Oliveira

et al. 2015

Front. Cell. Neurosci.

298

249

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Alzheimer’s disease (AD) is the most common form of dementia in the elderly, and affects millions of people worldwide. As the number of AD cases continues to increase in both developed and developing countries, finding therapies that effectively halt or reverse disease progression constitutes a major research and public health challenge. Since the identification of the amyloid-β peptide (Aβ) as the major component of the amyloid plaques that are characteristically found in AD brains, a major effort has aimed to determine whether and how Aβ leads to memory loss and cognitive impairment. A large body of evidence accumulated in the past 15 years supports a pivotal role of soluble Aβ oligomers (AβOs) in synapse failure and neuronal dysfunction in AD. Nonetheless, a number of basic questions, including the exact molecular composition of the synaptotoxic oligomers, the identity of the receptor(s) to which they bind, and the signaling pathways that ultimately lead to synapse failure, remain to be definitively answered. Here, we discuss recent advances that have illuminated our understanding of the chemical nature of the toxic species and the deleterious impact they have on synapses, and have culminated in the proposal of an Aβ oligomer hypothesis for Alzheimer’s pathogenesis. We also highlight outstanding questions and challenges in AD research that should be addressed to allow translation of research findings into effective AD therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Aβos As Synaptotoxins In Admentioning

confidence: 99%

Soluble amyloid-Î² oligomers as synaptotoxins leading to cognitive impairment in Alzheimerâ€™s disease

Ferreira

Lourenco

Oliveira

et al. 2015

Front. Cell. Neurosci.

298

249

View full text Add to dashboard Cite

show abstract

“…As the disease progress, the axonal transport is constantly reduced, and the general function of neurons is impaired. These changes decrease BDNF axonal transport, resulting in reduced availability of BDNF within the synaptic cleft and consequently diminished signaling through TrkB receptors [ 137 , 138 ]. BDNF mRNA and protein levels are also reduced in cognition-related structures such as hippocampus and frontal cortex, which corroborates BDNF depletion to be involved in the cognitive deficit leading to AD dementia [ 139 ].…”

Section: Bdnf In Neurodegenerative Disordersmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation

et al. 2018

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Brain-derived neurotrophic factor (BDNF) is one of the most studied neurotrophins in the healthy and diseased brain. As a result, there is a large body of evidence that associates BDNF with neuronal maintenance, neuronal survival, plasticity, and neurotransmitter regulation. Patients with psychiatric and neurodegenerative disorders often have reduced BDNF concentrations in their blood and brain. A current hypothesis suggests that these abnormal BDNF levels might be due to the chronic inflammatory state of the brain in certain disorders, as neuroinflammation is known to affect several BDNF-related signaling pathways. Activation of glia cells can induce an increase in the levels of pro- and antiinflammatory cytokines and reactive oxygen species, which can lead to the modulation of neuronal function and neurotoxicity observed in several brain pathologies. Understanding how neuroinflammation is involved in disorders of the brain, especially in the disease onset and progression, can be crucial for the development of new strategies of treatment. Despite the increasing evidence for the involvement of BDNF and neuroinflammation in brain disorders, there is scarce evidence that addresses the interaction between the neurotrophin and neuroinflammation in psychiatric and neurodegenerative diseases. This review focuses on the effect of acute and chronic inflammation on BDNF levels in the most common psychiatric and neurodegenerative disorders and aims to shed some light on the possible biological mechanisms that may influence this effect. In addition, this review will address the effect of behavior and pharmacological interventions on BDNF levels in these disorders.

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“…AβO-triggered decrease in dendritic spine density in vivo was also effectively blocked with MK-801 treatment 36 . Inhibition of P/Q- and N-type VGCCs prevented AβO-induced presynaptic calcium influx that specifically blocks brain-derived neurotrophic factor transport in axons 61 . In addition to promoting calcium entry from extracellular sources, AβOs also induced free calcium release from intracellular endoplasmic reticulum (ER) stores via ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate (IP 3 ) receptors 62 .…”

Section: Discussionmentioning

confidence: 93%

An acute functional screen identifies an effective antibody targeting amyloid-β oligomers based on calcium imaging

Wang

Kastanenka

Arbel‐Ornath

et al. 2018

Sci Rep

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Soluble amyloid β oligomers (AβOs) are widely recognized neurotoxins that trigger aberrant signaling in specific subsets of neurons, leading to accumulated neuronal damage and memory disorders in Alzheimer’s disease (AD). One of the profound downstream consequences of AβO-triggered events is dysregulation of cytosolic calcium concentration ([Ca2+]i), which has been implicated in synaptic failure, cytoskeletal abnormalities, and eventually neuronal death. We have developed an in vitro/in vivo drug screening assay to evaluate putative AβO-blocking candidates by measuring AβO-induced real-time changes in [Ca2+]i. Our screening assay demonstrated that the anti-AβO monoclonal antibody ACU3B3 exhibits potent blocking capability against a broad size range of AβOs. We showed that picomolar concentrations of AβOs were capable of increasing [Ca2+]i in primary neuronal cultures, an effect prevented by ACU3B3. Topical application of 5 nM AβOs onto exposed cortical surfaces also elicited significant calcium elevations in vivo, which was completely abolished by pre-treatment of the brain with 1 ng/mL (6.67 pM) ACU3B3. Our results provide strong support for the utility of this functional screening assay in identifying and confirming the efficacy of AβO-blocking drug candidates such as the human homolog of ACU3B3, which may emerge as the first experimental AD therapeutic to validate the amyloid oligomer hypothesis.

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Dendritic and axonal mechanisms of Ca²⁺ elevation impair BDNF transport in Aβ oligomer–treated hippocampal neurons

Cited by 32 publications

References 74 publications

Soluble amyloid-Î² oligomers as synaptotoxins leading to cognitive impairment in Alzheimerâ€™s disease

Soluble amyloid-Î² oligomers as synaptotoxins leading to cognitive impairment in Alzheimerâ€™s disease

Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation

An acute functional screen identifies an effective antibody targeting amyloid-β oligomers based on calcium imaging

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Dendritic and axonal mechanisms of Ca2+ elevation impair BDNF transport in Aβ oligomer–treated hippocampal neurons

Cited by 32 publications

References 74 publications

Soluble amyloid-Î² oligomers as synaptotoxins leading to cognitive impairment in Alzheimerâ€™s disease

Soluble amyloid-Î² oligomers as synaptotoxins leading to cognitive impairment in Alzheimerâ€™s disease

Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation

An acute functional screen identifies an effective antibody targeting amyloid-β oligomers based on calcium imaging

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Product

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Dendritic and axonal mechanisms of Ca²⁺ elevation impair BDNF transport in Aβ oligomer–treated hippocampal neurons