Neurobiology of Disease最新文献

Background: Parkinson's disease is typically diagnosed after substantial neurodegeneration despite early non-motor symptoms manifesting decades earlier. These changes offer a promising avenue for diagnostic exploration, especially within the eye, which has been proposed as a "window to the brain."

Objective: The aim was to identify biomarkers by validating the use of electroretinography, a non-invasive technique, to detect early retinal function anomalies reflecting central dysfunction.

Methods: Homozygous M83 transgenic mice (n = 10 males,11 females), overexpressing human A53T α-synuclein, underwent behavioral tests and electroretinography measurements. Histological evaluation was performed at four months to analyze synucleinopathies and neurodegeneration. Electroretinography was also conducted with idiopathic PD patients (mean age 63.35 ± 7.73; disease duration 4.15 ± 2.06; H&Y score 2.07 ± 0.59; n = 12 males, 8 females) and healthy age-matched controls (mean age 61.65 ± 8.39; n = 9 males, 11 females).

Results: Rodent electroretinography revealed reduced photopic b-wave, PhNR b-wave, and PhNR-wave amplitudes at two and four months, particularly in females, indicating bipolar and retinal ganglion cell impairment. Based on retinal histological assessment, these changes might arise from α-synuclein pathology occurring in outer retinal layers. Likewise, the scotopic b-wave and PhNR waveform were similarly impaired in female participants with Parkinson's disease. The scotopic oscillatory potentials isolated further identified an attenuated amacrine cell output in females.

Conclusions: Findings from both mice and human cohorts indicate that retinal functional impairments can be detected early in the progression of Parkinson's disease, particularly among females. These tools show promise in facilitating early diagnosis, disease monitoring, therapeutic intervention, and ultimately enhancing patient outcomes.

Background: Brainstem stroke accounts only 7-10 % of all ischemic stroke while it had more morbidity and mortality. As the predominant cellular component of nerve tracts, oligodendrocytes might provide some neuroprotection against ischemic injury in the context of brainstem stroke, but the underlying mechanism remains unclear.

Method: A mouse model of brainstem stroke was established, and single-cell RNA sequencing and spatial transcriptomic sequencing analysis were performed to elucidate the phenotype of oligodendrocytes within this context.

Results: Loss of oligodendrocytes led to neurological impairment following brainstem stroke, and subsequent proliferation of oligodendrocytes was observed. We identified a subcluster of Pros1⁺ oligodendrocytes, designated OLG8 cells. These cells increased in number after brainstem stroke and were enriched around the peri-infarct zone. OLG8 cells were derived from oligodendrocyte progenitor cells, and this process was found to be regulated by Myo1e. We found that OLG8 cells protected interneurons. Notably, the overexpression of Myo1e within OLG8 cells led to a marked reduction in infarct volume while simultaneously improving the recovery of neurological function.

Conclusion: In conclusion, we identified a novel cell subcluster, OLG8 cells, in the context of brainstem stroke, and found that overexpression of Myo1e alleviated ischemic injury by facilitating the differentiation of OLG8 cells. Our study provided insight into the mechanism of brainstem stroke.

Huntington's disease (HD) is a complex neurodegenerative disorder with cognitive and motor symptoms that typically manifest in adulthood. However, embryonic brain development impairments leading to cortical defects in HD mutation carriers has been shown recently supporting a neurodevelopmental component in HD. Despite HD is primarily recognized as a striatal pathology, developmental alterations in this structure, particularly during the early postnatal period, remain poorly understood. To fill this gap, we examined striatal development in newborn R6/1 mice. We found that D2 receptor-expressing indirect-pathway medium spiny neurons (D2-MSNs) present in the matrix striatal compartment undergo early morphological and electrophysiological maturation. Altered electrophysiological properties were also observed in newborn CAG140 mice. Additionally, we also observed a D2-MSN-selective reduction in glutamatergic cortico-striatal transmission at the beginning of the second postnatal week as well as a reduced projection of D2-MSNs onto the GPe at birth in R6/1 mice. All these alterations were transient with the circuit normalizing after the second postnatal week. These results identify a compartment- and cell-type specific defect in D2-MSNs maturation, which can contribute in their latter vulnerability, as this cell-type is the first to degenerate in HD during adulthood.

Alzheimer's Disease (AD) remains an overwhelming epidemiologic and economic burden on our healthcare systems, affecting an estimate of 11 % of individuals aged 65 years and older. Increasing evidence of the role of the blood-brain barrier (BBB) in AD pathology lends support to the vascular hypothesis of AD, which posits that damage to cerebral vasculature and impairments to cerebral blood flow are major contributors to neurodegeneration in AD. While the question remains whether the dysfunction of the BBB is the cause or consequence of the disease, understanding of the relationship between vascular pathology and AD is growing increasingly complex, warranting the need for better tools to study vasculature in AD. This review provides an overview of AD models in the context of studying vascular impairments and their relevance in pathology. Specifically, we summarize opportunities in in vitro models, cell sources, and phenotypic observations in sporadic and familial forms of AD. Further, we describe recent advances in generating models which recapitulate in vivo characteristics of the BBB in AD through the use of microfluidics, induced pluripotent stem cells (iPSC), and organoid technologies. Finally, we provide a searchable database of reported cell-based models of pathogenic AD gene variants.