Propagation of Tau Pathology in a Model of Early Alzheimer’s Disease

Calignon, Alix de; Polydoro, Manuela; Suárez‐Calvet, Marc; William, Christopher; Adamowicz, David H.; Kopeikina, Kathy J.; Pitstick, Rose; Sahara, Naruhiko; Ashe, Karen H.; Carlson, George A.; Spires‐Jones, Tara L.; Hyman, Bradley T.

doi:10.1016/j.neuron.2012.10.005

Cited by 236 publications

(347 citation statements)

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“…The molecular mechanisms driving the spread of pathology remain largely unknown. Two recent studies propose that (abnormal) tau protein can be transported trans-synaptically and can function prion-like in triggering tau tangle formation [58,59]. Our findings support a model in which the retrograde transport of locally synthesized ATF4 causes transcriptional changes in the neuronal cell bodies that eventually lead to neurodegeneration and loss of neurons.…”

Section: Neurodegenerative Disorderssupporting

confidence: 86%

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Baleriola

Hengst

2015

Neurotherapeutics

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Localized protein synthesis is a mechanism by which morphologically polarized cells react in a spatially confined and temporally acute manner to changes in their environment. During the development of the nervous system intra-axonal protein synthesis is crucial for the establishment of neuronal connections. In contrast, mature axons have long been considered as translationally inactive but upon nerve injury or under neurodegenerative conditions specific subsets of mRNAs are recruited into axons and locally translated. Intra-axonally synthesized proteins can have pathogenic or restorative and regenerative functions, and thus targeting the axonal translatome might have therapeutic value, for example in the treatment of spinal cord injury or Alzheimer's disease. In the case of Alzheimer's disease the local synthesis of the stress response transcription factor activating transcription factor 4 mediates the long-range retrograde spread of pathology across the brain, and inhibition of local Atf4 translation downstream of the integrated stress response might interfere with this spread. Several molecular tools and approaches have been developed to target specifically the axonal translatome by either overexposing proteins locally in axons or, conversely, knocking down selectively axonally localized mRNAs. Many questions about axonal translation remain to be answered, especially with regard to the mechanisms establishing specificity but, nevertheless, targeting the axonal translatome is a promising novel avenue to pursue in the development for future therapies for various neurological conditions.

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Section: Neurodegenerative Disorderssupporting

confidence: 86%

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Baleriola

Hengst

2015

Neurotherapeutics

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“…De Caglignon et al [44] verified the limited expression of this transgene using in situ hybridization, which was further verified by qPCR on laser captured neurons. The group observed tau pathology in young mice that was limited to the medial entorhinal cortex (MEC).…”

Section: Transcellular Spread Of Tau Pathology In Vitro and In Vivomentioning

confidence: 85%

“…To further explore the spread of tau pathology throughout the brain, two groups used a transgenic mouse model that restricts P301L tau expression to the entorhinal cortex (EC) [44,45]. De Caglignon et al [44] verified the limited expression of this transgene using in situ hybridization, which was further verified by qPCR on laser captured neurons.…”

Section: Transcellular Spread Of Tau Pathology In Vitro and In Vivomentioning

confidence: 99%

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

Kaufman

Diamond

2013

Neurotherapeutics

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“…Transgenic mice overexpressing P301L tau in the entorhinal cortex, for example, demonstrate de novo wild-type ptau in brain regions synaptically connected with the performant pathway. 45 Further, prion-like selfpropagating 'strains' of tau appear along neuroanatomical pathways following intracerebral inoculation of experimental mice transgenic for human tau. 46 Similar strain propagation of amyloid-β has been demonstrated with synthetic peptides, and suggested as basis for phenotypic variability to human AD.…”

Section: Cte As a Prion Diseasementioning

confidence: 99%

Chronic traumatic encephalopathy: A paradigm in search of evidence?

Castellani

2015

Laboratory Investigation

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Chronic traumatic encephalopathy (CTE) has been in the medical literature since the 1920s. It is characterized clinically by diverse neuropsychiatric symptoms, and pathologically by variable degrees of phosphorylated tau accumulation in the brain. The evolving paradigm for the pathogenesis of CTE suggests that concussion or subconcussion from athletic participation initiates a cascade of pathologic events, encompassing neuroinflammation and protein templating with trans-synaptic neurotoxicity. The end result is neurologic and neurobehavioral deterioration, often with self-harm. Although these concepts warrant further investigation, the available evidence permits no conclusions as regards the pathogenesis of the reported findings. Investigations into the role of premorbid or co-morbid neurodegenerative diseases has been limited to date, and in-depth genetic analyses have not been performed. The role of concussion or subconcussion if any, whether and how the condition progresses over time, the extent of phosphorylated tau in clinically normal athletes, the role of phosphorylated tau as a toxic species versus an inert disease response, and whether protein templating has any in vivo relevance remain to be elucidated.

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Propagation of Tau Pathology in a Model of Early Alzheimer’s Disease

Cited by 236 publications

References 0 publications

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

Chronic traumatic encephalopathy: A paradigm in search of evidence?

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