The influence of ApoE4 on the clinical outcomes and pathophysiology of degenerative cervical myelopathy

Desimone, Alexa Maria Lena; Hong, James; Brockie, Sydney; Yu, Wen-Ru; Laliberté, Alex M.; Fehlings, Michael G.

doi:10.1172/jci.insight.149227

Cited by 17 publications

(10 citation statements)

References 61 publications

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“…To gain insight into the early molecular changes associated with the pathophysiology of AD, we included two AD models from the same C57BL/6 background at three months. These include an earlyonset AD (EOAD) model (5xFAD) that overexpresses mutant human amyloid-beta precursor protein (APP) and human presenilin 1 (PS1) harboring multiple AD-associated mutations (Oakley et al, 2006); and a late-onset AD (LOAD) model (APOE*4/Trem2*R47H) that carries two of the highest risk factor mutations of LOAD, including a humanized ApoE knock-in allele and missense mutations in the mouse Trem2 gene (Desimone et al, 2021;Xiang et al, 2018). Nuclei were first extracted from the whole brain, then deposited to different wells for indexed reverse transcription (EasySci-RNA) or transposition (EasySci-ATAC), such that the first index identified the originating sample and assay type of any given well.…”

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confidence: 99%

A global view of aging and Alzheimer’s pathogenesis-associated cell population dynamics and molecular signatures in the human and mouse brains

Sziraki

Lee

et al. 2022

Preprint

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Although several studies have applied single-cell approaches to explore gene expression changes in aged brains, they were limited by the relatively shallow sampling of brain cell populations, and thus may have failed to capture aspects of the molecular signatures and dynamics of rare cell types associated with aging and diseases. Here, we set out to investigate the age-dependent dynamics of transcription and chromatin accessibility across diverse brain cell types. With EasySci, an extensively improved single-cell combinatorial indexing strategy, we profiled ~1.5 million single-cell transcriptomes and ~400,000 single-cell chromatin accessibility profiles across mouse brains spanning different ages, genotypes, and both sexes. With a novel computational framework designed for characterizing cellular subtypes based on the expression of both genes and exons, we identified > 300 cell subtypes and deciphered the underlying molecular programs and spatial locations of rare cell types (e.g., pinealocytes, tanycytes) and subtypes. Leveraging these data, we generate a global readout of age-dependent cell population dynamics with high cellular subtype resolution, providing insights into cell types that expand (e.g., rare astrocytes and vascular leptomeningeal cells in the olfactory bulb, reactive microglia and oligodendrocytes) or are depleted (e.g., neuronal progenitors, neuroblasts, committed oligodendrocyte precursors) as age progresses. Furthermore, we explored cell-type-specific responses to genetic perturbations associated with Alzheimer's disease (AD) and identify rare cell types depleted (e.g., mt-Cytb+, mt-Rnr2+ choroid plexus epithelial cells) or enriched (e.g., Col25a1+, Ndrg1+ interbrain and midbrain neurons) in both AD models. Key findings are consistent between males and females, validated across the transcriptome, chromatin accessibility, and spatial analyses. Finally, we profiled a total of 118,240 single-nuclei transcriptomes from twenty-four human brain samples derived from control and AD patients, revealing highly cell-type-specific and region-specific gene expression changes associated with AD pathogenesis. Critical AD-associated gene signatures were validated in both human and mice. In summary, these data comprise a rich resource for exploring cell-type-specific dynamics and the underlying molecular mechanisms in both normal and pathological mammalian aging.

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confidence: 99%

A global view of aging and Alzheimer’s pathogenesis-associated cell population dynamics and molecular signatures in the human and mouse brains

Sziraki

Lee

et al. 2022

Preprint

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“…Additionally, and similar to humans, the DCM mouse model presents with a marked impairment in gait [ 11 , 19 ], as well as in forelimb and hindlimb stepping function. Here the animals with DCM showed a two-fold increase in foot faults during the horizontal ladder walk test compared to the sham group ( Figure 2 A,B, * p < 0.05), indicating detectable neurological deficits related to stepping function.…”

Section: Resultsmentioning

confidence: 99%

“…In our DCM mouse model, impairment in manual dexterity and locomotor deficits have been observed around 4 weeks after DCM induction [ 11 , 19 ]. In this study, significant deterioration in base support was observed from 4 weeks onward when compared to their sham counterparts.…”

Section: Discussionmentioning

confidence: 99%

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Acute Systemic White Blood Cell Changes following Degenerative Cervical Myelopathy (DCM) in a Mouse Model

Ulndreaj

Ávila

Hong

et al. 2022

IJMS

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Degenerative cervical myelopathy (DCM) is caused by age-related degeneration of the cervical spine, causing chronic spinal cord compression and inflammation. The aim of this study was to assess whether the natural progression of DCM is accompanied by hematological changes in the white blood cell composition. If so, these changes can be used for diagnosis complementing established imaging approaches and for the development of treatment strategies, since peripheral immunity affects the progression of DCM. Gradual compression of the spinal cord was induced in C57B/L mice at the C5-6 level. The composition of circulating white blood cells was analyzed longitudinally at four time points after induction of DCM using flow cytometry. At 12 weeks, serum cytokine levels were measured using a Luminex x-MAP assay. Neurological impairment in the mouse model was also assessed using the ladder walk test and CatWalk. Stepping function (* p < 0.05) and overground locomotion (*** p < 0.001) were impaired in the DCM group. Importantly, circulating monocytes and T cells were affected primarily at 3 weeks following DCM. T cells were two-fold lower in the DCM group (*** p < 0.0006), whereas monocytes were four-fold increased (*** p < 0.0006) in the DCM compared with the sham group. Our data suggest that changes in white blood cell populations are modest, which is unique to other spinal cord pathologies, and precede the development of neurobehavioral symptoms.

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“…In contrast, the biopolymer polyurethane elastomer Aquaprene C works like an expandable material made of water-absorbing polyurethane elastomer that increases its volume more than 200% in 24 h inducing acute damage, different from the progression of the human pathology ( Kim et al, 2004 ; Ijima et al, 2017 ). Here, we used a synthetic aromatic polyether polymer that offers clinical advantages to model DCM in mice, such as the ability to nucleate the precipitation of phosphate anions emulating the progressive osteoid formation in accessible vertebral segments of implantation, resembling histopathological and behavioral features of clinical presentation ( Klironomos et al, 2011 ; Karadimas et al, 2013 ; Desimone et al, 2021 ; Laliberte et al, 2021 ; Ulndreaj et al, 2022 ). Using this model, we presented a systematic analysis of the pathobiology observed, including loss of motoneurons, motor impairment, and neuromuscular degeneration, as well as muscle loss and wasting ( Otsu, 1979 ; Karadimas et al, 2013 ; Badhiwala et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Impaired communication at the neuromotor axis during Degenerative Cervical Myelopathy

Ojeda,

Vergara,

Ávila

et al. 2024

Front. Cell. Neurosci.

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Degenerative Cervical Myelopathy (DCM) is a progressive neurological condition characterized by structural alterations in the cervical spine, resulting in compression of the spinal cord. While clinical manifestations of DCM are well-documented, numerous unanswered questions persist at the molecular and cellular levels. In this study, we sought to investigate the neuromotor axis during DCM. We use a clinically relevant mouse model, where after 3 months of DCM induction, the sensorimotor tests revealed a significant reduction in both locomotor activity and muscle strength compared to the control group. Immunohistochemical analyses showed alterations in the gross anatomy of the cervical spinal cord segment after DCM. These changes were concomitant with the loss of motoneurons and a decrease in the number of excitatory synaptic inputs within the spinal cord. Additionally, the DCM group exhibited a reduction in the endplate surface, which correlated with diminished presynaptic axon endings in the supraspinous muscles. Furthermore, the biceps brachii (BB) muscle exhibited signs of atrophy and impaired regenerative capacity, which inversely correlated with the transversal area of remnants of muscle fibers. Additionally, metabolic assessments in BB muscle indicated an increased proportion of oxidative skeletal muscle fibers. In line with the link between neuromotor disorders and gut alterations, DCM mice displayed smaller mucin granules in the mucosa layer without damage to the epithelial barrier in the colon. Notably, a shift in the abundance of microbiota phylum profiles reveals an elevated Firmicutes-to-Bacteroidetes ratio—a consistent hallmark of dysbiosis that correlates with alterations in gut microbiota-derived metabolites. Additionally, treatment with short-chain fatty acids stimulated the differentiation of the motoneuron-like NSC34 cell line. These findings shed light on the multifaceted nature of DCM, resembling a synaptopathy that disrupts cellular communication within the neuromotor axis while concurrently exerting influence on other systems. Notably, the colon emerges as a focal point, experiencing substantial perturbations in both mucosal barrier integrity and the delicate balance of intestinal microbiota.

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The influence of ApoE4 on the clinical outcomes and pathophysiology of degenerative cervical myelopathy

Cited by 17 publications

References 61 publications

A global view of aging and Alzheimer’s pathogenesis-associated cell population dynamics and molecular signatures in the human and mouse brains

A global view of aging and Alzheimer’s pathogenesis-associated cell population dynamics and molecular signatures in the human and mouse brains

Acute Systemic White Blood Cell Changes following Degenerative Cervical Myelopathy (DCM) in a Mouse Model

Impaired communication at the neuromotor axis during Degenerative Cervical Myelopathy

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