Dataset Information

Visualization of microbleeds with optical histology in mouse model of cerebral amyloid angiopathy.

ABSTRACT: Cerebral amyloid angiopathy (CAA) is a neurovascular disease that is strongly associated with an increase in the number and size of spontaneous microbleeds. Conventional methods of magnetic resonance imaging for detection of microbleeds, and positron emission tomography with Pittsburgh Compound B imaging for amyloid deposits, can separately demonstrate the presence of microbleeds and CAA in affected brains in vivo; however, there still is a critical need for strong evidence that shows involvement of CAA in microbleed formation. Here, we show in a Tg2576 mouse model of Alzheimer's disease, that the combination of histochemical staining and an optical clearing method called optical histology, enables simultaneous, co-registered three-dimensional visualization of cerebral microvasculature, microbleeds, and amyloid deposits. Our data suggest that microbleeds are localized within the brain regions affected by vascular amyloid deposits. All observed microhemorrhages (n=39) were in close proximity (0 to 144 ?m) with vessels affected by CAA. Our data suggest that the predominant type of CAA-related microbleed is associated with leaky or ruptured hemorrhagic microvasculature. The proposed methodological and instrumental approach will allow future study of the relationship between CAA and microbleeds during disease development and in response to treatment strategies.

SUBMITTER: Lo P

PROVIDER: S-EPMC4814270 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Visualization of microbleeds with optical histology in mouse model of cerebral amyloid angiopathy.

Lo Patrick P Crouzet Christian C Vasilevko Vitaly V Choi Bernard B

Microvascular research 20160210

Cerebral amyloid angiopathy (CAA) is a neurovascular disease that is strongly associated with an increase in the number and size of spontaneous microbleeds. Conventional methods of magnetic resonance imaging for detection of microbleeds, and positron emission tomography with Pittsburgh Compound B imaging for amyloid deposits, can separately demonstrate the presence of microbleeds and CAA in affected brains in vivo; however, there still is a critical need for strong evidence that shows involvemen ...[more]

PMID: 26876114

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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.

Project description:Cerebral amyloid angiopathy (CAA) involves cerebrovascular amyloid deposition and is classified into several types according to the amyloid protein involved. Of these, sporadic amyloid β-protein (Aβ)-type CAA is most commonly found in older individuals and in patients with Alzheimer's disease (AD). Cerebrovascular Aβ deposits accompany functional and pathological changes in cerebral blood vessels (CAA-associated vasculopathies). CAA-associated vasculopathies lead to development of hemorrhagic lesions [lobar intracerebral macrohemorrhage, cortical microhemorrhage, and cortical superficial siderosis (cSS)/focal convexity subarachnoid hemorrhage (SAH)], ischemic lesions (cortical infarction and ischemic changes of the white matter), and encephalopathies that include subacute leukoencephalopathy caused by CAA-associated inflammation/angiitis. Thus, CAA is related to dementia, stroke, and encephalopathies. Recent advances in diagnostic procedures, particularly neuroimaging, have enabled us to establish a clinical diagnosis of CAA without brain biopsies. Sensitive magnetic resonance imaging (MRI) methods, such as gradient-echo T2(*) imaging and susceptibility-weighted imaging, are useful for detecting cortical microhemorrhages and cSS. Amyloid imaging with amyloid-binding positron emission tomography (PET) ligands, such as Pittsburgh Compound B, can detect CAA, although they cannot discriminate vascular from parenchymal amyloid deposits. In addition, cerebrospinal fluid markers may be useful, including levels of Aβ40 for CAA and anti-Aβ antibody for CAA-related inflammation. Moreover, cSS is closely associated with transient focal neurological episodes (TFNE). CAA-related inflammation/angiitis shares pathophysiology with amyloid-related imaging abnormalities (ARIA) induced by Aβ immunotherapies in AD patients. This article reviews CAA and CAA-related disorders with respect to their epidemiology, pathology, pathophysiology, clinical features, biomarkers, diagnosis, treatment, risk factors, and future perspectives.

Project description:Background and purposeCerebral amyloid angiopathy (CAA) is a common cause of recurrent intracerebral hemorrhage in the elderly. Previous studies have shown that CAA induces inflammation and expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 (gelatinases) in amyloid-laden vessels. Here, we inhibited both using minocycline in CAA mouse models to determine whether spontaneous intracerebral hemorrhage could be reduced.MethodsTg2576 (n=16) and 5xFAD/ApoE4 knockin mice (n=16), aged 17 and 12 months, respectively, were treated with minocycline (50 mg/kg, IP) or saline every other day for 2 months. Brains were extracted and stained with X-34 (to quantify amyloid), Perls' blue (to quantify hemorrhage), and immunostained to examined β-amyloid peptide load, gliosis (glial fibrillary acidic protein [GFAP], Iba-1), and vascular markers of blood-brain barrier integrity (zonula occludins-1 [ZO-1] and collagen IV). Brain extracts were used to quantify mRNA for a variety of inflammatory genes.ResultsMinocycline treatment significantly reduced hemorrhage frequency in the brains of Tg2576 and 5xFAD/ApoE4 mice relative to the saline-treated mice, without affecting CAA load. Gliosis (GFAP and Iba-1 immunostaining), gelatinase activity, and expression of a variety of inflammatory genes (matrix metalloproteinase-9, NOX4, CD45, S-100b, and Iba-1) were also significantly reduced. Higher levels of microvascular tight junction and basal lamina proteins were found in the brains of minocycline-treated Tg2576 mice relative to saline-treated controls.ConclusionsMinocycline reduced gliosis, inflammatory gene expression, gelatinase activity, and spontaneous hemorrhage in 2 different mouse models of CAA, supporting the importance of matrix metalloproteinase-related and inflammatory pathways in intracerebral hemorrhage pathogenesis. As a Food and Drug Administration-approved drug, minocycline might be considered for clinical trials to test efficacy in preventing CAA-related intracerebral hemorrhage.

Dataset Information

Visualization of microbleeds with optical histology in mouse model of cerebral amyloid angiopathy.

Publications

Visualization of microbleeds with optical histology in mouse model of cerebral amyloid angiopathy.

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