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MFG-E8 (LACTADHERIN): a novel marker associated with cerebral amyloid angiopathy.

ABSTRACT: Brain accumulation of amyloid-beta (Aβ) is a crucial feature in Alzheimer´s disease (AD) and cerebral amyloid angiopathy (CAA), although the pathophysiological relationship between these diseases remains unclear. Numerous proteins are associated with Aβ deposited in parenchymal plaques and/or cerebral vessels. We hypothesized that the study of these proteins would increase our understanding of the overlap and biological differences between these two pathologies and may yield new diagnostic tools and specific therapeutic targets. We used a laser capture microdissection approach combined with mass spectrometry in the APP23 transgenic mouse model of cerebral-β-amyloidosis to specifically identify vascular Aβ-associated proteins. We focused on one of the main proteins detected in the Aβ-affected cerebrovasculature: MFG-E8 (milk fat globule-EGF factor 8), also known as lactadherin. We first validated the presence of MFG-E8 in mouse and human brains. Immunofluorescence and immunoblotting studies revealed that MFG-E8 brain levels were higher in APP23 mice than in WT mice. Furthermore, MFG-E8 was strongly detected in Aβ-positive vessels in human postmortem CAA brains, whereas MFG-E8 was not present in parenchymal Aβ deposits. Levels of MFG-E8 were additionally analysed in serum and cerebrospinal fluid (CSF) from patients diagnosed with CAA, patients with AD and control subjects. Whereas no differences were found in MFG-E8 serum levels between groups, MFG-E8 concentration was significantly lower in the CSF of CAA patients compared to controls and AD patients. Finally, in human vascular smooth muscle cells MFG-E8 was protective against the toxic effects of the treatment with the Aβ40 peptide containing the Dutch mutation. In summary, our study shows that MFG-E8 is highly associated with CAA pathology and highlights MFG-E8 as a new CSF biomarker that could potentially be used to differentiate cerebrovascular Aβ pathology from parenchymal Aβ deposition.

SUBMITTER: Marazuela P

PROVIDER: S-EPMC8444498 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundWe observed subarachnoid cerebrospinal fluid (CSF) hyperintensities at non-contrast 7-tesla (T) fluid-attenuated inversion recovery (FLAIR) MRI, frequently topographically associated with cortical superficial siderosis (cSS), in participants with cerebral amyloid angiopathy (CAA). To systemically evaluate these CSF hyperintensities we investigated their frequency and anatomical and temporal relationship with cSS on 7T and 3T MRI in hereditary Dutch-type CAA (D-CAA), sporadic CAA (sCAA), and non-CAA controls.MethodsCAA participants were included from two prospective natural history studies and non-CAA controls from a 7T study in healthy females and females with ischemic stroke. CSF hyperintensities were scored by two independent observers.ResultsWe included 38 sCAA participants (mean age 72y), 50 D-CAA participants (mean age 50y) and 44 non-CAA controls (mean age 53y, 15 with stroke). In total 27/38 (71 %, 95 %CI 56-84) sCAA and 23/50 (46 %, 95 %CI 33-60) D-CAA participants had subarachnoid CSF hyperintensities at baseline 7T. Most (96 %) of those had cSS, in 54 % there was complete topographical overlap with cSS. The remaining 46 % had ≥1 sulcus with CSF hyperintensities without co-localizing cSS. None of the healthy controls and 2/15 (13 %, 95 %CI 2-41, 100 % cSS overlap) of the stroke controls had CSF hyperintensities. In 85 % of the CAA participants CSF hyperintensities could retrospectively be identified at 3T. Of the 35 CAA participants with follow-up 7T after two years, 17/35 (49 %) showed increase and 6/35 (17 %) decrease of regional CSF hyperintensities. In 2/11 (18 %) of participants with follow-up who had baseline CSF hyperintensities without overlapping cSS, new cSS developed at those locations.ConclusionsSubarachnoid CSF hyperintensities at 7T FLAIR MRI occur frequently in CAA and are associated with cSS, although without complete overlap. We hypothesize that the phenomenon could be a sign of subtle plasma protein or blood product leakage into the CSF, resulting in CSF T1-shortening.

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.

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MFG-E8 (LACTADHERIN): a novel marker associated with cerebral amyloid angiopathy.

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