Neurobiology of disease
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Neurobiology of disease · Oct 2020
ReviewCircadian alterations in patients with neurodegenerative diseases: Neuropathological basis of underlying network mechanisms.
Circadian organization of physiology and behavior is an important biological process that allows organisms to anticipate and prepare for daily changes and demands. Disruptions in this system precipitates a wide range of health issues. In patients with neurodegenerative diseases, alterations of circadian rhythms are among the most common and debilitating symptoms. ⋯ Recent studies have examined the neuropathological status of the different neural components of the circuitry governing the generation of circadian rhythms in neurodegenerative diseases. In this review, we will dissect the potential contribution of dysfunctions in the different nodes of this circuitry to circadian alterations in patients with neurodegenerative diseases. A deeper understanding of these mechanisms will provide not only a better understanding of disease neuro-pathophysiology, but also hold the promise for developing effective and mechanisms-based therapies.
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Neurobiology of disease · Mar 2020
Sustained neuronal and microglial alterations are associated with diverse neurobehavioral dysfunction long after experimental brain injury.
Traumatic brain injury (TBI) can cause progressive neurodegeneration, sustained neuroinflammation and chronic neurological dysfunction. Few experimental studies have explored the long-term neurobehavioral and functional cellular changes beyond several months. The present study examined the effects of a single moderate-level TBI on functional outcome 8 months after injury. ⋯ Living neurons showed decreased expression of synaptophysin and postsynaptic density (PSD)-95, along with greater numbers of microtubule-associated protein light chain 3 (LC3)-positive autophagosomes and increased mitochondrial mass that suggest dysregulation of autophagy. In summary, the late neurobehavioral changes found after murine TBI are similar to those found chronically after moderate-severe human head injury. Importantly, such changes are associated with microglial dysfunction and changes in neuronal activity.
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Neurobiology of disease · Dec 2019
Periodic dietary restriction ameliorates amyloid pathology and cognitive impairment in PDAPP-J20 mice: Potential implication of glial autophagy.
Dietary restriction promotes cell regeneration and stress resistance in multiple models of human diseases. One of the conditions that could potentially benefit from this strategy is Alzheimer's disease, a chronic, progressive and prevalent neurodegenerative disease. Although there are no effective pharmacological treatments for this pathology, lifestyle interventions could play therapeutic roles. ⋯ In vitro experiments showed that nutrient restriction decreased astroglial and, indirectly, microglial NFκB activation in response to amyloid β peptides. Furthermore, nutrient restriction was able to preserve astroglial autophagic flux and to decrease intracellular amyloid after exposure to amyloid β peptides. Our results suggest neuroprotective effects of nutrient restriction in Alzheimer's disease, with modulation of glial activation and autophagy being potentially involved pathways.
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Neurobiology of disease · Dec 2019
RANTES-induced invasion of Th17 cells into substantia nigra potentiates dopaminergic cell loss in MPTP mouse model of Parkinson's disease.
Although Parkinson's disease (PD) is a progressive neurodegenerative disease, the disease does not progress or persist in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, the most common animal model of PD. Recently, we have described that supplementation of regulated on activation, normal T cell expressed and secreted (RANTES), a chemokine known to drive infiltration of T cells, induces persistent nigrostriatal pathology in MPTP mouse model. However, which particular T cell subsets are recruited to the substantia nigra (SN) by RANTES is not known. ⋯ RANTES-mediated aggravation of nigral TH neurons also paralleled with significant DA loss in striatum and locomotor deficits in MPTP-intoxicated Rag1-/- mice receiving Th17 cells. Finally, we demonstrate that levels of IL-17 (a Th17-specific cytokine) and RANTES are higher in serum of PD patients than age-matched controls and that RANTES positively correlated with IL-17 in serum of PD patients. Together, these results highlight the importance of RANTES-Th17 pathway in progressive dopaminergic neuronal loss and associated PD pathology.
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Neurobiology of disease · Oct 2019
Time course and magnitude of alpha-synuclein inclusion formation and nigrostriatal degeneration in the rat model of synucleinopathy triggered by intrastriatal α-synuclein preformed fibrils.
Animal models that accurately recapitulate the accumulation of alpha-synuclein (α-syn) inclusions, progressive neurodegeneration of the nigrostriatal system and motor deficits can be useful tools for Parkinson's disease (PD) research. The preformed fibril (PFF) synucleinopathy model in rodents generally displays these PD-relevant features, however, the magnitude and predictability of these events is far from established. We therefore sought to optimize the magnitude of α-syn accumulation and nigrostriatal degeneration, and to understand the time course of both. ⋯ Bilateral injection of 16 μg α-syn PFFs resulted in symmetric bilateral degeneration equivalent to the ipsilateral nigral degeneration observed following unilateral 16 μg PFF injection (~50% loss). Bilateral PFF injections additionally resulted in alterations in several gait analysis parameters. These α-syn PFF parameters can be applied to generate a reproducible synucleinopathy model in rats with which to study pathogenic mechanisms and vet potential disease-modifying therapies.