Mechanical injuries of neurons induce tau mislocalization to dendritic spines and tau-dependent synaptic dysfunction

Braun, Nicholas; Yao, Katherine R.; Alford, Patrick W.; Liao, Dezhi

doi:10.1073/pnas.2008306117

Cited by 35 publications

(43 citation statements)

References 72 publications

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“…Another option, supported by recent evidence, is that some tau is physiologically present in dendritic spines [ 174 ], and that this proportion of tau is the one that mediates LTD, exerting its function in synaptic plasticity. In addition, mechanical injuries of neurons lead to mislocalization of tau to dendritic spines and tau-dependent synaptic dysfunction, mediated by GSK-3 (and CDK5) tau phosphorylation [ 179 ]. In neurodegenerative disorders such as AD and other dementias, tau becomes hyperphosphorylated, detaches from MTs.…”

Section: Interplay Between Gsk-3 and Tau During Ltdmentioning

confidence: 99%

GSK-3 and Tau: A Key Duet in Alzheimer’s Disease

Sayas

Ávila

2021

Cells

138

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Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase with a plethora of substrates. As a modulator of several cellular processes, GSK-3 has a central position in cell metabolism and signaling, with important roles both in physiological and pathological conditions. GSK-3 has been associated with a number of human disorders, such as neurodegenerative diseases including Alzheimer’s disease (AD). GSK-3 contributes to the hyperphosphorylation of tau protein, the main component of neurofibrillary tangles (NFTs), one of the hallmarks of AD. GSK-3 is further involved in the regulation of different neuronal processes that are dysregulated during AD pathogenesis, such as the generation of amyloid-β (Aβ) peptide or Aβ-induced cell death, axonal transport, cholinergic function, and adult neurogenesis or synaptic function. In this review, we will summarize recent data about GSK-3 involvement in these processes contributing to AD pathology, mostly focusing on the crucial interplay between GSK-3 and tau protein. We further discuss the current development of potential AD therapies targeting GSK-3 or GSK-3-phosphorylated tau.

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Section: Interplay Between Gsk-3 and Tau During Ltdmentioning

confidence: 99%

GSK-3 and Tau: A Key Duet in Alzheimer’s Disease

Sayas

Ávila

2021

Cells

138

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“…Several studies have also used in vitro platforms to investigate the potential mechanisms by which cell injury can lead to tau-related pathologies. For example, in one such study a stretch model employing rodent hippocampal cells was used to investigate the effect of injury on tauopathy ( Braun et al, 2020 ). This study revealed that mechanical stretching of cultured neurons resulted in tau mislocalization to dendritic spines which results in subsequent synaptic dysfunction.…”

Section: In Vitro Models Of Traumatic Brain Injurymentioning

confidence: 99%

The Emergence of Model Systems to Investigate the Link Between Traumatic Brain Injury and Alzheimer’s Disease

Srinivasan

Brafman

2022

Front. Aging Neurosci.

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Numerous epidemiological studies have demonstrated that individuals who have sustained a traumatic brain injury (TBI) have an elevated risk for developing Alzheimer’s disease and Alzheimer’s-related dementias (AD/ADRD). Despite these connections, the underlying mechanisms by which TBI induces AD-related pathology, neuronal dysfunction, and cognitive decline have yet to be elucidated. In this review, we will discuss the various in vivo and in vitro models that are being employed to provide more definite mechanistic relationships between TBI-induced mechanical injury and AD-related phenotypes. In particular, we will highlight the strengths and weaknesses of each of these model systems as it relates to advancing the understanding of the mechanisms that lead to TBI-induced AD onset and progression as well as providing platforms to evaluate potential therapies. Finally, we will discuss how emerging methods including the use of human induced pluripotent stem cell (hiPSC)-derived cultures and genome engineering technologies can be employed to generate better models of TBI-induced AD.

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“…Traumatic brain injury (TBI) is the strongest environmental risk factor for the accelerated development of neurodegenerative processes. Computational modelling provided insights into the cognitive decline and the presence of neurofibrillary tangles of the protein tau in the brains upon repetitive TBI [ 87 ]. The impacting high-strain rate deformation alone could induce tau mislocalization to dendritic spines and synaptic deficits in cultured hippocampal neurons which was inhibitable on the signalling level [ 87 ].…”

Section: Introductionmentioning

confidence: 99%

“…Computational modelling provided insights into the cognitive decline and the presence of neurofibrillary tangles of the protein tau in the brains upon repetitive TBI [ 87 ]. The impacting high-strain rate deformation alone could induce tau mislocalization to dendritic spines and synaptic deficits in cultured hippocampal neurons which was inhibitable on the signalling level [ 87 ]. Thus, a mechanistic pathway directly relating mechanical deformation of neurons to tau-mediated synaptic impairments and a potential exploitable therapeutic approach to improve repetitive TBI consequences has now been provided [ 87 ].…”

Section: Introductionmentioning

confidence: 99%

“…The impacting high-strain rate deformation alone could induce tau mislocalization to dendritic spines and synaptic deficits in cultured hippocampal neurons which was inhibitable on the signalling level [ 87 ]. Thus, a mechanistic pathway directly relating mechanical deformation of neurons to tau-mediated synaptic impairments and a potential exploitable therapeutic approach to improve repetitive TBI consequences has now been provided [ 87 ]. A recently described molecular memory system (C–C-chemokine receptor type 5 (CCR5) signalling) was tested for its role in recovery after TBI [ 88 ].…”

Section: Introductionmentioning

confidence: 99%

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The future of basic science in orthopaedics and traumatology: Cassandra or Prometheus?

et al. 2021

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Orthopaedic and trauma research is a gateway to better health and mobility, reflecting the ever-increasing and complex burden of musculoskeletal diseases and injuries in Germany, Europe and worldwide. Basic science in orthopaedics and traumatology addresses the complete organism down to the molecule among an entire life of musculoskeletal mobility. Reflecting the complex and intertwined underlying mechanisms, cooperative research in this field has discovered important mechanisms on the molecular, cellular and organ levels, which subsequently led to innovative diagnostic and therapeutic strategies that reduced individual suffering as well as the burden on the society. However, research efforts are considerably threatened by economical pressures on clinicians and scientists, growing obstacles for urgently needed translational animal research, and insufficient funding. Although sophisticated science is feasible and realized in ever more individual research groups, a main goal of the multidisciplinary members of the Basic Science Section of the German Society for Orthopaedics and Trauma Surgery is to generate overarching structures and networks to answer to the growing clinical needs. The future of basic science in orthopaedics and traumatology can only be managed by an even more intensified exchange between basic scientists and clinicians while fuelling enthusiasm of talented junior scientists and clinicians. Prioritized future projects will master a broad range of opportunities from artificial intelligence, gene- and nano-technologies to large-scale, multi-centre clinical studies. Like Prometheus in the ancient Greek myth, transferring the elucidating knowledge from basic science to the real (clinical) world will reduce the individual suffering from orthopaedic diseases and trauma as well as their socio-economic impact.

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Mechanical injuries of neurons induce tau mislocalization to dendritic spines and tau-dependent synaptic dysfunction

Cited by 35 publications

References 72 publications

GSK-3 and Tau: A Key Duet in Alzheimer’s Disease

GSK-3 and Tau: A Key Duet in Alzheimer’s Disease

The Emergence of Model Systems to Investigate the Link Between Traumatic Brain Injury and Alzheimer’s Disease

The future of basic science in orthopaedics and traumatology: Cassandra or Prometheus?

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