Dataset Information

Cerebral vascular leak in a mouse model of amyloid neuropathology.

ABSTRACT: In Alzheimer's disease (AD), there is increasing evidence of blood-brain barrier (BBB) compromise, usually observed as 'microbleeds' correlated with amyloid plaque deposition and apoE-?4 status, raising the possibility of nanotherapeutic delivery. Molecular probes have been used to study neurovascular leak, but this approach does not adequately estimate vascular permeability of nanoparticles. We therefore characterized cerebrovascular leaks in live APP+ transgenic animals using a long circulating ?100?nm nanoparticle computed tomography (CT) contrast agent probe. Active leaks fell into four categories: (1) around the dorsomedial cerebellar artery (DMCA), (2) around other major vessels, (3) nodular leaks in the cerebral cortex, and (4) diffuse leaks. Cortical leaks were uniformly more frequent in the transgenic animals than in age-matched controls. Leaks around vessels other than the DMCA were more frequent in older transgenics compared with younger ones. All other leaks were equally prevalent across genotypes independent of age. Ten days after injection, 4 to 5??g of the dose was estimated to be present in the brain, roughly a half of which was in locations other than the leaky choroid plexus, and associated with amyloid deposition in older animals. These results suggest that amyloid deposition and age increase delivery of nanoparticle-borne reagents to the brain, in therapeutically relevant amounts.

SUBMITTER: Tanifum EA

PROVIDER: S-EPMC4269723 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Cerebral vascular leak in a mouse model of amyloid neuropathology.

Tanifum Eric A EA Starosolski Zbigniew A ZA Fowler Stephanie W SW Jankowsky Joanna L JL Annapragada Ananth V AV

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20140723 10

In Alzheimer's disease (AD), there is increasing evidence of blood-brain barrier (BBB) compromise, usually observed as 'microbleeds' correlated with amyloid plaque deposition and apoE-ɛ4 status, raising the possibility of nanotherapeutic delivery. Molecular probes have been used to study neurovascular leak, but this approach does not adequately estimate vascular permeability of nanoparticles. We therefore characterized cerebrovascular leaks in live APP+ transgenic animals using a long circulatin ...[more]

PMID: 25052555

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Project description:BackgroundAccumulation and deposition of ?-amyloid peptides (A?) in the brain is a central event in the pathogenesis of Alzheimer's disease (AD). Besides the parenchymal pathology, A? is known to undergo active transport across the blood-brain barrier and cerebral amyloid angiopathy (CAA) is a prominent feature in the majority of AD. Although impaired cerebral blood flow (CBF) has been implicated in faulty A? transport and clearance, and cerebral hypoperfusion can exist in the pre-clinical phase of Alzheimer's disease (AD), it is still unclear whether it is one of the causal factors for AD pathogenesis, or an early consequence of a multi-factor condition that would lead to AD at late stage. To study the potential interaction between faulty CBF and amyloid accumulation in clinical-relevant situation, we generated a new amyloid precursor protein (APP) knock-in allele that expresses humanized A? and a Dutch mutation in addition to Swedish/London mutations and compared this line with an equivalent knock-in line but in the absence of the Dutch mutation, both crossed onto the PS1M146V knock-in background.ResultsIntroduction of the Dutch mutation results in robust CAA and parenchymal A? pathology, age-dependent reduction of spatial learning and memory deficits, and CBF reduction as detected by fMRI. Direct manipulation of CBF by transverse aortic constriction surgery on the left common carotid artery caused differential changes in CBF in the anterior and middle region of the cortex, where it is reduced on the left side and increased on the right side. However these perturbations in CBF resulted in the same effect: both significantly exacerbate CAA and amyloid pathology.ConclusionsOur study reveals a direct and positive link between vascular and parenchymal A?; both can be modulated by CBF. The new APP knock-in mouse model recapitulates many symptoms of AD including progressive vascular and parenchymal A? pathology and behavioral deficits in the absence of APP overexpression.

Project description:Cerebral amyloid angiopathy (CAA), defined as the accumulation of amyloid-beta (A?) on the vascular wall, is a major pathology of Alzheimer's disease (AD) and has been thought to be caused by the failure of A? clearance. Although two types of perivascular clearance mechanisms, intramural periarterial drainage (IPAD) and the perivascular cerebrospinal fluid (CSF) influx, have been identified, the exact contribution of CAA on perivascular clearance is still not well understood. In this study, we investigated the effect of CAA on the structure and function of perivascular clearance systems in the APP/PS1 transgenic mouse model. To investigate the pathological changes accompanied by CAA progression, the key elements of perivascular clearance such as the perivascular basement membrane, vascular smooth muscle cells (vSMCs), and vascular pulsation were evaluated in middle-aged (7-9 months) and old-aged (19-21 months) mice using in vivo imaging and immunofluorescence staining. Changes in IPAD and perivascular CSF influx were identified by ex vivo fluorescence imaging after dextran injection into the parenchyma or cisterna magna. Amyloid deposition on the vascular wall disrupted the integrity and morphology of the arterial basement membrane. With CAA progression, vascular pulsation was augmented, and conversely, vSMC coverage was decreased. These pathological changes were more pronounced in the surface arteries with earlier amyloid accumulation than in penetrating arteries. IPAD and perivascular CSF influx were impaired in the middle-aged APP/PS1 mice and further aggravated in old age, showing severely impaired tracer influx and efflux patterns. Reduced clearance was also observed in old wild-type mice without changing the tracer distribution pattern in the influx and efflux pathway. These findings suggest that CAA is not merely a consequence of perivascular clearance impairment, but rather a contributor to this process, causing changes in arterial function and structure and increasing AD severity.

Dataset Information

Cerebral vascular leak in a mouse model of amyloid neuropathology.

Publications

Cerebral vascular leak in a mouse model of amyloid neuropathology.

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