Age-dependent neurovascular abnormalities and altered microglial morphology in the YAC128 mouse model of Huntington disease

Franciosi, Sonia; Ryu, Jae K.; Shim, Yaein Amy; Hill, Austin; Connolly, Colúm; Hayden, Michael R.; McLarnon, James G.; Leavitt, Blair R.

doi:10.1016/j.nbd.2011.09.003

Cited by 107 publications

(77 citation statements)

References 46 publications

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“…In contrast, the immunohistological studies in humans and mice models revealed significantly increased vessel density in the cortical and striatal regions; the BBB likely was intact and functional (Franciosi et al, 2012;Lin et al, 2013). Chronic deposition of peripheral lipopolysaccharides, which is typical for presymptomatic HD, had no effect on the density or length of vessels but had significant effects on vessel integrity (Franciosi et al, 2012). The observed narrowing of the vessel lumens was explained as due to the increased thickness of basal lamina, which reflected increased smooth-muscle cell proliferation and a decrease in the activity of proteases involved in extracellular-matrix turnover, resulting in an accumulation of vessel wall components such as collagen IV (Franciosi et al, 2012).…”

Section: Huntington Diseasementioning

confidence: 84%

“…In particular, reduced perfusion was found in areas of the brain cortex that are closely associated with higher neural activity . In contrast, the immunohistological studies in humans and mice models revealed significantly increased vessel density in the cortical and striatal regions; the BBB likely was intact and functional (Franciosi et al, 2012;Lin et al, 2013). Chronic deposition of peripheral lipopolysaccharides, which is typical for presymptomatic HD, had no effect on the density or length of vessels but had significant effects on vessel integrity (Franciosi et al, 2012).…”

Section: Huntington Diseasementioning

confidence: 94%

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Microcirculation of the brain: morphological assessment in degenerative diseases and restoration processes

Kolinko¹,

Krakorova

Cendelín³

et al. 2015

Reviews in the Neurosciences

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AbstractBrain microcirculation plays an important role in the pathogenesis of various brain diseases. Several specific features of the circulation in the brain and its functions deserve special attention. The brain is extremely sensitive to hypoxia, and brain edema is more dangerous than edema in other tissues. Brain vessels are part of the blood-brain barrier, which prevents the penetration of some of the substances in the blood into the brain tissue. Herein, we review the processes of angiogenesis and the changes that occur in the brain microcirculation in the most prevalent neurodegenerative diseases. There are no uniform vascular changes in the neurodegenerative diseases. In some cases, the vascular changes are secondary consequences of the pathological process, but they could also be involved in the pathogenesis of the primary disease and contribute to the degeneration of neurons, based on their quantitative characteristics. Additionally, we described the stereological methods that are most commonly used for generating qualitative and quantitative data to assess changes in the microvascular bed of the brain.

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Section: Huntington Diseasementioning

confidence: 84%

Section: Huntington Diseasementioning

confidence: 94%

Microcirculation of the brain: morphological assessment in degenerative diseases and restoration processes

Kolinko¹,

Krakorova

Cendelín³

et al. 2015

Reviews in the Neurosciences

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“…For example, comparison of BBB permeability values between the aggressive R6/2 model of HD and wild-type littermates revealed no significant differences (CepedaPrado et al, 2012). Interestingly, however, Lin et al recently reported that R6/2 mice as well as humans with HD exhibit detectable enhancements in microvasculature densities (Lin et al, 2013), and progressive neurovascular abnormalities have previously been reported in YAC128 mice (Franciosi et al, 2012), which suggests some degree of diseaserelated dysfunction in the HD neurovascular unit. As reported elsewhere, SEMA4D blocking antibody preserves the integrity of the BBB under inflammatory conditions by preventing downregulation of Claudin-5 and breakdown of endothelial tight junctions (Smith et al, 2014).…”

Section: Discussionmentioning

confidence: 97%

Anti-semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease

Southwell

Franciosi

Villanueva

et al. 2015

Neurobiology of Disease

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Huntington disease (HD) is an inherited, fatal neurodegenerative disease with no disease-modifying therapy currently available. In addition to characteristic motor deficits and atrophy of the caudate nucleus, signature hallmarks of HD include behavioral abnormalities, immune activation, and cortical and white matter loss. The identification and validation of novel therapeutic targets that contribute to these degenerative cellular processes may lead to new interventions that slow or even halt the course of this insidious disease. Semaphorin 4D (SEMA4D) is a transmembrane signaling molecule that modulates a variety of processes central to neuroinflammation and neurodegeneration including glial cell activation, neuronal growth cone collapse and apoptosis of neural precursors, as well as inhibition of oligodendrocyte migration, differentiation and process formation. Therefore, inhibition of SEMA4D signaling could reduce CNS inflammation, increase neuronal outgrowth and enhance oligodendrocyte maturation, which may be of therapeutic benefit in the treatment of several neurodegenerative diseases, including HD. To that end, we evaluated the preclinical therapeutic efficacy of an anti-SEMA4D monoclonal antibody, which prevents the interaction between SEMA4D and its receptors, in the YAC128 transgenic HD mouse model. Anti-SEMA4D treatment ameliorated neuropathological signatures, including striatal atrophy, cortical atrophy, and corpus callosum atrophy and prevented testicular degeneration in YAC128 mice. In parallel, a subset of behavioral symptoms was improved in anti-SEMA4D treated YAC128 mice, including reduced anxiety-like behavior and rescue of cognitive deficits. There was, however, no discernible effect on motor deficits. The preservation of brain gray and white matter and improvement in behavioral measures in YAC128 mice treated with anti-SEMA4D suggest that this approach could represent a viable therapeutic strategy for the treatment of HD. Importantly, this work provides in vivo demonstration that inhibition of pathways initiated by SEMA4D constitutes a novel approach to moderation of neurodegeneration.

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“…Hyperperfusion has been reported in HD patients and mice, 5,[35][36][37][38][39] and is observed as increased vessel density, 1,5 cerebral blood volume, 40 or CBF. 36 The results from our cellular studies indicate that inflammation-prone astrocytes play a key role in the abnormal HD brain NVU.…”

Section: Discussionmentioning

confidence: 98%

Aberrant astrocytes impair vascular reactivity in Huntington disease

Hsiao

Chen

Huang

et al. 2015

Annals of Neurology

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Age-dependent neurovascular abnormalities and altered microglial morphology in the YAC128 mouse model of Huntington disease

Cited by 107 publications

References 46 publications

Microcirculation of the brain: morphological assessment in degenerative diseases and restoration processes

Microcirculation of the brain: morphological assessment in degenerative diseases and restoration processes

Anti-semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease

Aberrant astrocytes impair vascular reactivity in Huntington disease

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