Transformation of diffuse beta-amyloid precursor protein and beta-amyloid deposits to plaques in the thalamus following transient occlusion of the middle cerebral artery in rats

Groen, Thomas van; Puurunen, Kirsi; Mäki, Hanna-Mari; Sivenius, Juhani; Jolkkonen, Jukka

doi:10.1038/sj.jcbfm.9591524.0213

Cited by 35 publications

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“…12 Perilesional APP/Aβ labeling disappears with longer follow-up (≥7 days). 6 In addition, APP maturation is enhanced during the acute phase, indicative of elevations in APP trafficking from the perilesional cortex via the descending axons to the thalamus. 11 Thus, after effective cell homing to ischemic hemisphere after intraarterial infusion, 3 it may be that the presence of BMMSCs at this particular time point (48 hours) further activates perilesional corticothalamic neurons, resulting in Aβ and calcium overflow in the thalamus in turn worsening the secondary pathology.…”

Section: Discussionmentioning

confidence: 99%

“…To assess the thalamic accumulation of Aβ, immunohistochemistry using rabbit anti-rodent antibody (Aβ3-16, #9151, Covance, Dedham, MA, USA) was performed as previously described. 6 Calcium accumulation in the thalamus after MCAO was assessed by the Alizarin red method. 8 Analysis Stained brain sections were analyzed in a blind manner with the Adobe Photoshop CC software (San Jose, CA, USA).…”

Section: Histologymentioning

confidence: 99%

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Unexpected Complication in a Rat Stroke Model: Exacerbation of Secondary Pathology in the Thalamus by Subacute Intraarterial Administration of Human Bone Marrow-Derived Mesenchymal Stem Cells

Mitkari

Kerkelä

Nystedt

et al. 2015

J Cereb Blood Flow Metab

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This study examined whether human bone marrow mesenchymal stromal/stem cells (BMMSCs) could alleviate the secondary pathology in the thalamus after middle cerebral artery occlusion (MCAO) in rats. Atypical accumulation of both amyloid-β (Aβ) and calcium in the thalamus was significantly higher in rats receiving the BMMSCs infusion 48 hours after MCAO as compared with the vehicle MCAO group. The elevated Aβ/calcium accumulation correlated with the level of impaired sensorimotor function. Although secondary pathology in the thalamus seems to be rodent specific, it needs to be taken into account because it may impair long-term behavioral recovery and negate therapeutic treatment effects. Flow & Metabolism (2015) 35, 363-366; doi:10.1038/jcbfm.2014; published online 7 January 2015 Journal of Cerebral BloodKeywords: β-amyloid; calcium; cell therapy; cerebral ischemia; secondary pathology INTRODUCTION At present therapeutic options in stroke are extremely limited and thus much effort is being directed at developing innovative treatments, such as cell therapies. In particular, intravascular cell therapy is a promising approach for the treatment of stroke and is claimed to achieve an efficient and wide cell engraftment in case of large or multiple lesions. 1 Since it is relatively noninvasive, application of this approach would be feasible in stroke therapy.We have previously shown that intravenous infusion of human umbilical cord blood cells in rats after middle cerebral artery occlusion (MCAO) results in the accumulation of cells primarily in the lungs. 2 The lung entrapment can be circumvented by intraarterial cell infusion, which can target cells to the ischemic brain as shown by intraarterial infusion of human bone marrow-derived stem cells (BMMSCs). 3 The most effective therapeutic time window for intraarterial cell transplantation is not known. Acute cell infusion after stroke has been postulated to be neuroprotective, whereas cell delivery at later time points (424 hours) may enhance brain repair mechanisms. 4 Late cell delivery is also thought to target the delayed secondary degeneration occurring in remote areas of the brain such as the ventroposterolateral and ventroposteromedial thalamic nuclei. 5,6 In most animal models, the thalamus is spared from the acute ischemic damage but the region is affected because it has synaptic connections with the primary injury site. The widespread corticostriatal damage results in retrograde and anterograde degeneration, 7 which is also associated with atypical accumulation of amyloid precursor protein (APP) and amyloid-β (Aβ) in the thalamus. 6 The initially diffuse APP and Aβ staining becomes later transformed into dense plaque-like deposits in the thalamus. Interestingly, the APP/Aβ depositions show an overlapping distribution with calcium deposits. 8 The secondary pathology in the thalamus takes place in a delayed manner after the ischemic event and thus represents a novel target for stroke therapy. The aim of the present work was to study whether human BMMSCs (1 × 10 6 ...

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Section: Discussionmentioning

confidence: 99%

Section: Histologymentioning

confidence: 99%

Unexpected Complication in a Rat Stroke Model: Exacerbation of Secondary Pathology in the Thalamus by Subacute Intraarterial Administration of Human Bone Marrow-Derived Mesenchymal Stem Cells

Mitkari

Kerkelä

Nystedt

et al. 2015

J Cereb Blood Flow Metab

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“…In the ipsilateral thalamus, A␤ accumulated abnormally and aggregated to plaque-like deposits for up to 9 months after MCA occlusion. 39 We investigated the association of A␤ with secondary thalamic damage and found that administration of a functional ␥-secretase inhibitor significantly reduced A␤ deposits and neuronal loss in the thalamus, suggesting that A␤ deposits may be associated with secondary thalamic damage. 40 In addition to A␤, Nogo-A, which can inhibit axonal growth, also has been shown to be upregulated within 4 weeks after MCA occlusion.…”

Section: Zhang Et Al Secondary Lesions After Cerebral Infarctionmentioning

confidence: 99%

Secondary Neurodegeneration in Remote Regions After Focal Cerebral Infarction

Zhang

Zhang²,

Xing³

et al. 2012

Stroke

184

170

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“…Further observations from rat models of acute middle cerebral artery territory infarction showing a transient increase in APP, A␤, and reactive astrocytes in peri-infarct regions 24 lend support to a third hypothesis suggesting that the focal A␤ accumulation represents an acute inflammatory response produced by focal ischemic stress. Reactive astrocytes with APP immunoreactivity can be observed in the periphery of acute infarcts from day 3 after middle cerebral artery occlusion.…”

Section: Patterns Of Focal Pib Retentionmentioning

confidence: 80%

Subacute Ischemic Stroke Is Associated With Focal ¹¹ C PiB Positron Emission Tomography Retention But Not With Global Neocortical Aβ Deposition

Rowe

Villemagne

et al. 2012

Stroke

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Background and Purpose-Conflicting evidence exists as to whether focal cerebral ischemia contributes to cerebral amyloid deposition. We aimed to look at A␤ deposits, detected by N-methyl-2-(4Ј-methylaminophenyl)-6-hydroxybenzothiazole (PiB) positron emission tomography, in patients with recent ischemic stroke. Specifically, we hypothesized that patients with recent ischemic stroke have higher local and neocortical PiB positron emission tomography retention and that this may be associated with major vascular risk factors. Methods-Ischemic stroke patients were studied using PiB positron emission tomography within 30 days and compared to age-matched controls. Distribution volume ratio maps were created using Logan graphical analysis with the cerebellar cortex as a reference. Results-Among the 21 ischemic stroke patients (median age, 76 years; interquartile range, 68 -77), the ipsilateral peri-infarct region PiB retention was higher compared to the contralateral mirror region, with a PiB distribution volume ratio difference of 0.29 (95% CI, 0.2-0.44; Pϭ0.001) at median 10 (interquartile range, 7-14) days after stroke. Two patients also had higher PiB retention within the infarct compared to the contralateral side. There was no difference in the neocortical PiB retention elsewhere in the brain among ischemic stroke patients compared with 22 age-matched normal controls (Pϭ0.22). Among the risk factors in the ischemic stroke patients, diabetes was associated with a higher neocortical PiB retention (Spearman Rhoϭ0.48; 95% CI, 0.28 -0.72). Conclusions-PiB retention was higher in the peri-infarct region among patients with recent ischemic stroke. This did not translate into a higher global neocortical PiB retention except possibly in patients with diabetes. The cause of the focal PiB retention is uncertain and requires further investigation. (Stroke. 2012;43:1341-1346.)

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Transformation of diffuse beta-amyloid precursor protein and beta-amyloid deposits to plaques in the thalamus following transient occlusion of the middle cerebral artery in rats

Cited by 35 publications

References 0 publications

Unexpected Complication in a Rat Stroke Model: Exacerbation of Secondary Pathology in the Thalamus by Subacute Intraarterial Administration of Human Bone Marrow-Derived Mesenchymal Stem Cells

Unexpected Complication in a Rat Stroke Model: Exacerbation of Secondary Pathology in the Thalamus by Subacute Intraarterial Administration of Human Bone Marrow-Derived Mesenchymal Stem Cells

Secondary Neurodegeneration in Remote Regions After Focal Cerebral Infarction

Subacute Ischemic Stroke Is Associated With Focal ¹¹ C PiB Positron Emission Tomography Retention But Not With Global Neocortical Aβ Deposition

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Transformation of diffuse beta-amyloid precursor protein and beta-amyloid deposits to plaques in the thalamus following transient occlusion of the middle cerebral artery in rats

Cited by 35 publications

References 0 publications

Unexpected Complication in a Rat Stroke Model: Exacerbation of Secondary Pathology in the Thalamus by Subacute Intraarterial Administration of Human Bone Marrow-Derived Mesenchymal Stem Cells

Unexpected Complication in a Rat Stroke Model: Exacerbation of Secondary Pathology in the Thalamus by Subacute Intraarterial Administration of Human Bone Marrow-Derived Mesenchymal Stem Cells

Secondary Neurodegeneration in Remote Regions After Focal Cerebral Infarction

Subacute Ischemic Stroke Is Associated With Focal 11 C PiB Positron Emission Tomography Retention But Not With Global Neocortical Aβ Deposition

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Subacute Ischemic Stroke Is Associated With Focal ¹¹ C PiB Positron Emission Tomography Retention But Not With Global Neocortical Aβ Deposition