Amyloid-Beta Induced Changes in Vesicular Transport of BDNF in Hippocampal Neurons

Seifert, Bianca; Eckenstaler, Robert; Rönicke, Raik; Leschik, Julia; Lutz, Beat; Reymann, Klaus G.; Leßmann, Volkmar; Brigadski, Tanja

doi:10.1155/2016/4145708

Cited by 27 publications

(16 citation statements)

References 94 publications

(118 reference statements)

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“…It remains to be determined to what extent and at what time the exposure to various peptides affects mitochondrial ROS production or calcium buffering in respect to changes in axonal trafficking. Our data are consistent with recently reported observations that anterograde and retrograde transport of brain-derived neurotrophic factor (BDNF) - containing vesicles but not the activity-dependent release of BDNF from these vesicles was affected after the acute treatment with Aβ42 peptides in neurons (Seifert et al, 2016). Indeed, we have shown that partial inhibition of mitochondrial complex I with small molecules induces a positive metabolic adaptation resulting in a reduction of pTau and Aβ levels, and the activity of GSK3β in multiple mouse models of AD (Zhang et al, 2015).…”

Section: Discussionsupporting

confidence: 93%

Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane

Zhang

Trushin

Christensen

et al. 2018

Neurobiology of Disease

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Inhibition of mitochondrial axonal trafficking by amyloid beta (Aβ) peptides has been implicated in early pathophysiology of Alzheimer’s Disease (AD). Yet, it remains unclear whether the loss of motility inevitably induces the loss of mitochondrial function, and whether restoration of axonal trafficking represents a valid therapeutic target. Moreover, while some investigations identify Aβ oligomers as the culprit of trafficking inhibition, others propose that fibrils play the detrimental role. We have examined the effect of a panel of Aβ peptides with different mutations found in familial AD on mitochondrial motility in primary cortical mouse neurons. Peptides with higher propensity to aggregate inhibit mitochondrial trafficking to a greater extent with fibrils inducing the strongest inhibition. Binding of Aβ peptides to the plasma membrane was sufficient to induce trafficking inhibition where peptides with reduced plasma membrane binding and internalization had lesser effect on mitochondrial motility. We also found that Aβ peptide with Icelandic mutation A673T affects axonal trafficking of mitochondria but has very low rates of plasma membrane binding and internalization in neurons, which could explain its relatively low toxicity. Inhibition of mitochondrial dynamics caused by Aβ peptides or fibrils did not instantly affect mitochondrial bioenergetic and function. Our results support a mechanism where inhibition of axonal trafficking is initiated at the plasma membrane by soluble low molecular weight Aβ species and is exacerbated by fibrils. Since trafficking inhibition does not coincide with the loss of mitochondrial function, restoration of axonal transport could be beneficial at early stages of AD progression. However, strategies designed to block Aβ aggregation or fibril formation alone without ensuring the efficient clearance of soluble Aβ may not be sufficient to alleviate the trafficking phenotype.

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Section: Discussionsupporting

confidence: 93%

Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane

Zhang

Trushin

Christensen

et al. 2018

Neurobiology of Disease

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“…Lower levels of BDNF correlate with poor cognitive status and higher amyloid‐beta protein (Beeri & Sonnen, ; Buchman et al ., ). Soluble Aβ oligomers impair both vesicular and axonal BDNF trafficking resulting in disruption of BDNF signaling, which underlies the synaptic dysfunction displayed in AD (Poon et al ., ; Seifert et al ., ). BDNF plays a critical role in the formation and survival of neurons, maintenance of structural and functional plasticity and is a key player of plasticity and memory (Korte et al ., ; Rex et al ., ; Park & Poo, ).…”

Section: Discussionmentioning

confidence: 97%

Epigenetic regulation by G9a/GLP complex ameliorates amyloid‐beta 1‐42 induced deficits in long‐term plasticity and synaptic tagging/capture in hippocampal pyramidal neurons

2017

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SummaryAltered epigenetic mechanisms are implicated in the cognitive decline associated with neurodegenerative diseases such as in Alzheimer's disease (AD). AD is the most prevalent form of dementia worldwide; amyloid plaques and neurofibrillary tangles are the histopathological hallmarks of AD. We have recently reported that the inhibition of G9a/GLP complex promotes long‐term potentiation (LTP) and its associative mechanisms such as synaptic tagging and capture (STC). However, the role of this complex in plasticity impairments remains elusive. Here, we investigated the involvement of G9a/GLP complex in alleviating the effects of soluble Amyloid‐β 1‐42 oligomers (oAβ) on neuronal plasticity and associativity in the CA1 region of acute hippocampal slices from 5‐ to 7‐week‐old male Wistar rats. Our findings demonstrate that the regulation of G9a/GLP complex by inhibiting its catalytic activity reverses the amyloid‐β oligomer‐induced deficits in late‐LTP and STC. This is achieved by releasing the transcription repression of the brain‐derived neurotrophic factor (Bdnf) gene. The catalytic inhibition of G9a/GLP complex leads to the upregulation of Bdnf expression in the slices treated with oAβ. This further ensures the availability of BDNF that subsequently binds its receptor tyrosine kinase B (TrkB) and maintains the late‐LTP. Furthermore, the capture of BDNF by weakly activated synapses re‐establishes STC. Our findings regarding the reinstatement of functional plasticity and associativity in AD‐like conditions provide the first evidence for the role of G9a/GLP complex in AD. We propose G9a/GLP complex as the possible target for preventing oAβ‐induced plasticity deficits in hippocampal neurons.

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“…Seifert and colleagues also reported impairments in both the anterograde and retrograde transport of BDNF-containing vesicles in hippocampal neurons derived from another AD mouse model (5xFAD) with increased Aβ expression. In the study, a fast action (within 5 min) of Aβ on the transport was also revealed [ 168 ]. Gan et al proposed Ca 2+ -dependent mechanisms of the disruption of BDNF transport induced by Aβ oligomers.…”

Section: Bdnf/trkb Transport As a Therapeutic Target Of Neurodegementioning

confidence: 99%

Actions of Brain-Derived Neurotrophin Factor in the Neurogenesis and Neuronal Function, and Its Involvement in the Pathophysiology of Brain Diseases

Numakawa

Odaka

Adachi

2018

IJMS

233

138

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It is well known that brain-derived neurotrophic factor, BDNF, has an important role in a variety of neuronal aspects, such as differentiation, maturation, and synaptic function in the central nervous system (CNS). BDNF stimulates mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), phosphoinositide-3kinase (PI3K), and phospholipase C (PLC)-gamma pathways via activation of tropomyosin receptor kinase B (TrkB), a high affinity receptor for BDNF. Evidence has shown significant contributions of these signaling pathways in neurogenesis and synaptic plasticity in in vivo and in vitro experiments. Importantly, it has been demonstrated that dysfunction of the BDNF/TrkB system is involved in the onset of brain diseases, including neurodegenerative and psychiatric disorders. In this review, we discuss actions of BDNF and related signaling molecules on CNS neurons, and their contributions to the pathophysiology of brain diseases.

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Amyloid-Beta Induced Changes in Vesicular Transport of BDNF in Hippocampal Neurons

Cited by 27 publications

References 94 publications

Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane

Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane

Epigenetic regulation by G9a/GLP complex ameliorates amyloid‐beta 1‐42 induced deficits in long‐term plasticity and synaptic tagging/capture in hippocampal pyramidal neurons

Actions of Brain-Derived Neurotrophin Factor in the Neurogenesis and Neuronal Function, and Its Involvement in the Pathophysiology of Brain Diseases

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