Stroke-induced opposite and age-dependent changes of vessel-associated markers in co-morbid transgenic mice with Alzheimer-like alterations

Hawkes, Cheryl A.; Michalski, Dominik; Anders, Rebecca; Nissel, Sabine; Grosche, Jens; Bechmann, Ingo; Carare, Roxana O.; Härtig, Wolfgang

doi:10.1016/j.expneurol.2013.09.020

Cited by 35 publications

(34 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies have shown increased lesion volumes after middle cerebral artery occlusion in db/db mice (Chen et al, 2011) and morphological, as well as, functional alterations have been detected in AD mice after induced ischemia or stroke (Garcia-Alloza et al, 2011;Hawkes et al, 2013). Our data are in accordance with epidemiological studies showing that risk factors for vascular disease, including T2D (Luchsinger et al, 2007), are also risk factors for dementia.…”

Section: Discussionsupporting

confidence: 95%

Central vascular disease and exacerbated pathology in a mixed model of type 2 diabetes and Alzheimer's disease

Ramos-Rodríguez

Jiménez-Palomares

Murillo‐Carretero

et al. 2015

Psychoneuroendocrinology

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 95%

Central vascular disease and exacerbated pathology in a mixed model of type 2 diabetes and Alzheimer's disease

Ramos-Rodríguez

Jiménez-Palomares

Murillo‐Carretero

et al. 2015

Psychoneuroendocrinology

View full text Add to dashboard Cite

“…These results are consistent with previous studies in AD mice documenting neurovascular uncoupling: astrocyte endfeet swell and retract from CAA-laden vessels (but not from CAA-free vessels) in ArcAβ mice, 32 and greater disruption is seen after cerebral ischemia in 3xTg mice than in age-matched wild-type controls. 33 Third, we documented that CAA and neuritic plaque load in aged Tg2576 mice was not acutely altered by MCAO. Taken together, these data strongly indicate that CAA’s pathological effect on cerebrovascular function produced worse CBF deficits during and immediately following MCAO, which likely relates to the inability of nearby CAA-laden cerebral arterioles to provide collateral CBF through autoregulatory vasodilation.…”

Section: Discussionmentioning

confidence: 77%

Cerebral Amyloid Angiopathy Increases Susceptibility to Infarction After Focal Cerebral Ischemia in Tg2576 Mice

Zhou

Johnson

Vellimana

et al. 2014

Stroke

View full text Add to dashboard Cite

We and others have shown that soluble amyloid-β peptide (Aβ) and cerebral amyloid angiopathy (CAA) cause significant cerebrovascular dysfunction in mutant amyloid precursor protein (APP) mice, and that these deficits are greater in aged APP mice having CAA compared to young APP mice lacking CAA. Aβ in young APP mice also increases infarction following focal cerebral ischemia, but the impact of CAA on ischemic brain injury is unknown. To determine this, we assessed cerebrovascular reactivity, cerebral blood flow (CBF), and extent of infarction and neurological deficits following transient middle cerebral artery occlusion (MCAO) in aged APP mice having extensive CAA versus young APP mice lacking CAA (and aged-matched littermate controls). We found that aged APP mice have more severe cerebrovascular dysfunction that is CAA-dependent, have greater CBF compromise during and immediately following MCAO, and develop larger infarctions after MCAO. These data indicate CAA induces a more severe form of cerebrovascular dysfunction than Aβ alone, leading to intra- and post-ischemic CBF deficits that ultimately exacerbate cerebral infarction. Our results shed mechanistic light on human studies identifying CAA as an independent risk factor for ischemic brain injury.

show abstract

“…Thereby, the filament model in mice (Longa et al, 1989 ) allowed non-invasive induction of focal cerebral ischemia and led to reproducible infarction in the territory of the middle cerebral artery (Longa et al, 1989 ; Durukan and Tatlisumak, 2007 ; Engel et al, 2011 ), enabling robust quantifications on cellular reactions. Applying this model, our group already described ischemia-associated changes in endothelial cells, up-regulation of Coll IV in basal membranes and loss of aquaporin 4 in astrocytic endfeet 24 h after ischemia induction (Hawkes et al, 2013 ). Furthermore, we recently observed alterations on cytoskeletal elements as visualized by tau-immunoreactivity and abolished PNs in the nucleus reticularis thalami due to permanent focal cerebral ischemia (Härtig et al, 2016 ; Michalski et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…Of note, this concept also involves the adjacent extracellular matrix (ECM) which is known to critically impact on a variety of cellular functions (del Zoppo, 2009 ). Based on the NVU concept, our own histochemical analyses after experimental stroke in mice revealed significant alterations of vascular components (Hawkes et al, 2013 ; Krueger et al, 2015 ), microtubule-associated protein tau (Michalski et al, 2016 ) and vesicular neurotransmitter transporters (Michalski et al, 2013 ). In a first set of experiments that characterized ischemic consequences to the ECM, we were able to show significant alterations of ECM constituents—i.e., degraded perineuronal nets (PNs)—in the subcortical nucleus reticularis thalami (Härtig et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Damaged Neocortical Perineuronal Nets Due to Experimental Focal Cerebral Ischemia in Mice, Rats and Sheep

Härtig

Mages

Aleithe

et al. 2017

Front. Integr. Neurosci.

Self Cite

View full text Add to dashboard Cite

As part of the extracellular matrix (ECM), perineuronal nets (PNs) are polyanionic, chondroitin sulfate proteoglycan (CSPG)-rich coatings of certain neurons, known to be affected in various neural diseases. Although these structures are considered as important parts of the neurovascular unit (NVU), their role during evolution of acute ischemic stroke and subsequent tissue damage is poorly understood and only a few preclinical studies analyzed PNs after acute ischemic stroke. By employing three models of experimental focal cerebral ischemia, this study was focused on histopathological alterations of PNs and concomitant vascular, glial and neuronal changes according to the NVU concept. We analyzed brain tissues obtained 1 day after ischemia onset from: (a) mice after filament-based permanent middle cerebral artery occlusion (pMCAO); (b) rats subjected to thromboembolic MACO; and (c) sheep at 14 days after electrosurgically induced focal cerebral ischemia. Multiple fluorescence labeling was applied to explore simultaneous alterations of NVU and ECM. Serial mouse sections labeled with the net marker Wisteria floribunda agglutinin (WFA) displayed largely decomposed and nearly erased PNs in infarcted neocortical areas that were demarcated by up-regulated immunoreactivity for vascular collagen IV (Coll IV). Subsequent semi-quantitative analyses in mice confirmed significantly decreased WFA-staining along the ischemic border zone and a relative decrease in the directly ischemia-affected neocortex. Triple fluorescence labeling throughout the three animal models revealed up-regulated Coll IV and decomposed PNs accompanied by activated astroglia and altered immunoreactivity for parvalbumin, a calcium-binding protein in fast-firing GABAergic neurons which are predominantly surrounded by neocortical PNs. Furthermore, ischemic neocortical areas in rodents simultaneously displayed less intense staining of WFA, aggrecan, the net components neurocan, versican and the cartilage link protein (CRTL) as well as markers in net-bearing neurons such as the potassium channel subunit Kv3.1b and neuronal nuclei (NeuN). In summary, theconsistent observations based on three different stroke models confirmed that PNs are highly sensitive constituents of the NVU along with impaired associated GABAergic neurons. These results suggest that PNs could be promising targets of future stroke treatment, and further studies should address their reorganization and plasticity in both stabilizing the acute stroke as well as supportive effects during the chronic phase of stroke.

show abstract

Stroke-induced opposite and age-dependent changes of vessel-associated markers in co-morbid transgenic mice with Alzheimer-like alterations

Cited by 35 publications

References 90 publications

Central vascular disease and exacerbated pathology in a mixed model of type 2 diabetes and Alzheimer's disease

Central vascular disease and exacerbated pathology in a mixed model of type 2 diabetes and Alzheimer's disease

Cerebral Amyloid Angiopathy Increases Susceptibility to Infarction After Focal Cerebral Ischemia in Tg2576 Mice

Damaged Neocortical Perineuronal Nets Due to Experimental Focal Cerebral Ischemia in Mice, Rats and Sheep

Contact Info

Product

Resources

About