Cerebral Vascular Leak in a Mouse Model of Amyloid Neuropathology

Tanifum, Eric A.; Starosolski, Zbigniew; Fowler, Stephanie; Jankowsky, Joanna L.; Annapragada, Ananth

doi:10.1038/jcbfm.2014.125

Cited by 24 publications

(19 citation statements)

References 38 publications

(45 reference statements)

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“…Most microbleeds in EFAD mice were co-localized within Aβ deposits, also seen in another FAD model by dye-visualization of blood leaks (Tanifum et al, 2014). The correlations of microbleed numbers and of the CAA load with human Aβ suggest that increased Aβ levels drive cerebrovascular degeneration with blood-brain barrier (BBB) leakage.…”

Section: Discussionmentioning

confidence: 64%

The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice

Cacciottolo

Christensen

Moser

et al. 2016

Neurobiology of Aging

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The APOE4 allele confers greater risk of Alzheimer’s Disease (AD) for women than men, in conjunction with greater clinical deficits per unit of AD neuropathology (plaques, tangles). Cerebral microbleeds, which contribute to cognitive dysfunctions during AD, also show APOE4 excess, but sex-APOE allele interactions are not described. We report that elderly men diagnosed for mild cognitive impairment (MCI) and AD showed a higher risk of cerebral cortex microbleeds with APOE4 allele dose effect in two clinical cohorts (ADNI and KIDS). Sex-APOE interactions were further analyzed in EFAD mice carrying human APOE alleles and familial AD genes. At 7 months, E4FAD mice had cerebral cortex microbleeds with female excess, in contrast to humans. Cerebral amyloid angiopathy (CAA), plaques, and soluble Aβ also showed female excess. Both the cerebral microbleeds and CAA increased in proportion to individual Aβ load. In humans, the opposite sex bias of APOE4 allele for microbleeds vs the plaques and tangles is the first example of organ-specific, sex-linked APOE allele effects, and further shows AD as a uniquely human condition.

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Section: Discussionmentioning

confidence: 64%

The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice

Cacciottolo

Christensen

Moser

et al. 2016

Neurobiology of Aging

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“…For quantitative analysis of CT images, CT signal was converted into iodine concentration using a normalization factor as per methods described previously [15,16]. The normalization factor was determined by the slope of the line that best fit the plot of CT signal and iodine concentration in the phantom series.…”

Section: Methodsmentioning

confidence: 99%

Heterogeneous Uptake of Nanoparticles in Mouse Models of Pediatric High-Risk Neuroblastoma

et al. 2016

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Liposomal chemotherapeutics are exemplified by DOXIL® are commonly used in adult cancers. While these agents exhibit improved safety profile compared to their free drug counterparts, their treatment response rates have been ~ 20%, often attributed to the heterogeneous intratumoral uptake and distribution of liposomal nanoparticles. Non-invasive and quantitative monitoring of the uptake and distribution of liposomal nanoparticles in solid tumors could allow for patient stratification and personalized cancer nanomedicine. In this study, the variability of liposomal nanoparticle intratumoral distribution and uptake in orthotopic models of pediatric neuroblastoma was investigated using a liposomal nanoprobe visualized by high-resolution computed tomography (CT). Two human neuroblastoma cell lines (NGP: a MYCN-amplified line, and SH-SY5Y a MYCN non-amplified line) were implanted in the renal capsule of nude mice to establish the model. Intratumoral nanoparticle uptake was measured at tumor ages 1, 2, 3 and 4 weeks post implantation. The locations of uptake within the tumor were mapped in the 3-dimensional reconstructed images. Total uptake was measured by integration of the x-ray absorption signal over the intratumoral uptake locations. Both tumor models showed significant variation in nanoparticle uptake as the tumors aged. Observation of the uptake patterns suggested that the nanoparticle uptake was dominated by vascular leak at the surface/periphery of the tumor, and localized, heterogeneous vascular leak in the interior of the tumor. Slow growing SH-SY5Y tumors demonstrated uptake that correlated directly with the tumor volume. Faster growing NGP tumor uptake did not correlate with any tumor geometric parameters, including tumor volume, tumor surface area, and R30 and R50, measures of uptake localized to the interior of the tumor. However, uptake for both SH-SY5Y and NGP tumors correlated almost perfectly with the leak volume, as measured by CT. These results suggest that the uptake of nanoparticles is heterogeneous and not governed by tumor geometry. An imaging nanoprobe remains the best measure of nanoparticle uptake in these tumor models.

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“…Animal studies using neuropathology, imaging and staining have provided evidence for BBB impairment both in transgenic mouse models of β-amyloidosis [31,32,[143][144][145], and tauopathy [146]. Moreover, these studies have shown that BBB impairment occurs early during disease progression, before onset of Aβ deposition, CAA and cognitive impairment [145].…”

Section: Vascular Integrity In Ad: the Failing Shieldmentioning

confidence: 99%

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

Klohs

2019

Neurodegener Dis

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Background: Cerebrovascular disease is a common comorbidity in patients with Alzheimer's disease (AD). It is believed to contribute additively to the cognitive impairment and to lower the threshold for the development of dementia. However, accumulating evidence suggests that dysfunction of the cerebral vasculature and AD neuropathology interact in multiple ways. Vascular processes even proceed AD neuropathology, implicating a causal role in the etiology of AD. Thus, the review aims to provide an integrated view on vascular dysfunction in AD. Summary: In AD, the cerebral vasculature undergoes pronounced cellular, morphological and structural changes, which alters regulation of blood flow, vascular fluid dynamics and vessel integrity. Stiffening of central blood vessels lead to transmission of excessive pulsatile energy to the brain microvasculature, causing endorgan damage. Moreover, a dysregulated hemostasis and chronic vascular inflammation further impede vascular function, where its mediators interact synergistically. Changes of the cerebral vasculature are triggered and driven by systemic vascular abnormalities that are part of aging, and which can be accelerated and aggravated by cardiovascular diseas-es. Key Messages: In AD, the cerebral vasculature is the locus where multiple pathogenic processes converge and contribute to cognitive impairment. Understanding the molecular mechanism and pathophysiology of vascular dysfunction in AD and use of vascular blood-based and imaging biomarker in clinical studies may hold promise for future prevention and therapy of the disease.

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Cerebral Vascular Leak in a Mouse Model of Amyloid Neuropathology

Cited by 24 publications

References 38 publications

The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice

The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice

Heterogeneous Uptake of Nanoparticles in Mouse Models of Pediatric High-Risk Neuroblastoma

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

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