Distribution of Misfolded Prion Protein Seeding Activity Alone Does Not Predict Regions of Neurodegeneration

Alibhai, James; Blanco, Richard A.; Barria, Marcelo A.; Piccardo, Pedro; Caughey, Byron; Perry, V. Hugh; Freeman, Tom C.; Manson, Jean

doi:10.1371/journal.pbio.1002579

Cited by 54 publications

(62 citation statements)

References 57 publications

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“…Given the current understanding of the variability in glial gene expression among brain regions, a greater understanding of the glial response in different brain regions during the progression of disease could reveal novel aspects and improve our understanding regarding the potential of glial targeting for therapeutic intervention. Indeed, a study in our laboratory showed that glial cell responses are altered during disease progression in brain regions that are either susceptible or show resilience to neurodegeneration, even when the misfolded protein is detected in all brain regions tested (26). The expression of a number of microglial genes is differentially altered in brain regions undergoing neurodegeneration overlapping with those identified in other studies of prion disease and AD (66,141,(144)(145)(146)(147).…”

Section: Expression Profile Of Glial Cells During Neurodegenerative Dmentioning

confidence: 56%

“…Much evidence now exists to suggest that misfolded protein alone may not be sufficient to induce neurodegeneration. We have shown that misfolded proteins accumulate in both degenerating and non-degenerating regions of the brain (26). Thus, one important question is, "what leads to resilience and susceptibility in different brain regions?…”

Section: The Complexity Of the Brainmentioning

confidence: 99%

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Unravelling the glial response in the pathogenesis of Alzheimer's disease

2018

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Alzheimer's disease is a progressive, incurable neurodegenerative disease targeting specific neuronal populations within the brain while neighboring neurons appear unaffected. The focus for defining mechanisms has therefore been on the pathogenesis in affected neuronal populations and developing intervention strategies to prevent their cell death. However, there is growing recognition of the importance of glial cells in the development of pathology. Determining exactly how glial cells are involved in the disease process and the susceptibility of the aging brain provides unprecedented challenges. The present review examines recent studies attempting to unravel the glial response during the course of disease and how this action may dictate the outcome of neurodegeneration. The importance of regional heterogeneity of glial cells within the CNS during healthy aging and disease is examined to understand how the glial cells may contribute to neuronal susceptibility or resilience during the neurodegenerative process.—Alibhai, J. D., Diack, A. B., Manson, J. C. Unravelling the glial response in the pathogenesis of Alzheimer's disease. 32, 5766–5777 (2018). http://www.fasebj.org

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Section: Expression Profile Of Glial Cells During Neurodegenerative Dmentioning

confidence: 56%

Section: The Complexity Of the Brainmentioning

confidence: 99%

Unravelling the glial response in the pathogenesis of Alzheimer's disease

2018

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“…; Alibhai et al . ; Groveman et al . ), which means that the observed seeding capacity, similar in different groups of mice does not necessarily reflect that their levels of infectivity are also comparable.…”

Section: Discussionmentioning

confidence: 99%

Cellulose ether treatment in vivo generates chronic wasting disease prions with reduced protease resistance and delayed disease progression

Hannaoui

Arifin

Chang

et al. 2019

Journal of Neurochemistry

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Chronic wasting disease (CWD) is a prion disease of free‐ranging and farmed cervids that is highly contagious because of extensive prion shedding and prion persistence in the environment. Previously, cellulose ether compounds (CEs) have been shown to significantly extend the survival of mice inoculated with mouse‐adapted prion strains. In this study, we used CEs, TC‐5RW, and 60SH‐50, in vitro and in vivo to assess their efficacy to interfere with CWD prion propagation. In vitro, CEs inhibited CWD prion amplification in a dose‐dependent manner. Transgenic mice over‐expressing elk PrPC (tgElk) were injected subcutaneously with a single dose of either of the CEs, followed by intracerebral inoculation with different CWD isolates from white tailed deer, mule deer, or elk. All treated groups showed a prolonged survival of up to more than 30 % when compared to the control group regardless of the CWD isolate used for infection. The extended survival in the treated groups correlated with reduced proteinase K resistance of prions. Remarkably, passage of brain homogenates from treated or untreated animals in tgElk mice resulted in a prolonged life span of mice inoculated with homogenates from CE‐treated mice (of + 17%) even in the absence of further treatment. Besides the delayed disease onset upon passage in TgElk mice, the reduced proteinase K resistance was maintained but less pronounced. Therefore, these compounds can be very useful in limiting the spread of CWD in captive and wild‐ranging cervids.

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“…The spread of α-synuclein is not strictly determined by synaptic connectivity, but rather must be dictated by other factors [29]. Alibhai et al have demonstrated the accumulation of misfolded proteins alone does not define targeting of neurodegeneration, which instead results only when misfolded protein accompanies microglia response [30]. The reactive microglia within the SN are associated with phagocytosing DA neurons and the deposition of α-synuclein in PD [31].…”

Section: Discussionmentioning

confidence: 99%

White matter damage and systemic inflammation in Parkinson’s disease

Chiang

Chen

et al. 2017

BMC Neurosci

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BackgroundSystemic inflammation and white matter (WM) alterations have been noted as effects of Parkinson’s disease (PD). This study sought to evaluate WM integrity in PD patients using diffusion tensor imaging (DTI) and to assess its relationship with systemic inflammation.MethodsSixty-six patients with PD (23 men and 43 women) and 67 healthy volunteers (29 men and 38 women) underwent blood sampling to quantify inflammatory markers and DTI scans to determine fiber integrity. The inflammatory markers included leukocyte apoptosis, as well as cellular and serum adhesion molecules, in each peripheral blood sample. DTI-related indices [including fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD)] were derived from DTI scans. The resulting FA maps were compared using voxel-based statistics to determine differences between the PD and control groups. The differences in the DTI indices, clinical severity, and inflammatory markers were correlated.ResultsExploratory group-wise comparison between the two groups revealed that the PD patients exhibited extensive DTI index differences. Low FA accompanied by high RD and MD, without significant differences in AD, suggesting a demyelination process, were found in the parietal, occipital, cerebellar, and insular WM of the PD patients. The declined DTI indices were significantly correlated with increased clinical disease severity, adhesion molecules, and leukocyte apoptosis.ConclusionsPatients with PD experience WM integrity damage in vulnerable regions, and these impairments are associated with increased disease severity and systemic inflammation. The possible interactions among them may represent variant neuronal injuries and their consequent processes in PD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-017-0367-y) contains supplementary material, which is available to authorized users.

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Distribution of Misfolded Prion Protein Seeding Activity Alone Does Not Predict Regions of Neurodegeneration

Cited by 54 publications

References 57 publications

Unravelling the glial response in the pathogenesis of Alzheimer's disease

Unravelling the glial response in the pathogenesis of Alzheimer's disease

Cellulose ether treatment in vivo generates chronic wasting disease prions with reduced protease resistance and delayed disease progression

White matter damage and systemic inflammation in Parkinson’s disease

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