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UNC5C variants are associated with cerebral amyloid angiopathy.

ABSTRACT: OBJECTIVE:To determine whether common genetic variants in UNC5C, a recently identified late-onset Alzheimer disease (LOAD) dementia susceptibility gene, are associated with AD susceptibility or AD-related clinical/pathologic phenotypes. METHODS:We used data from deceased individuals of European descent who participated in the Religious Orders Study or the Rush Memory and Aging Project (n = 1,288). We examined whether there were associations between single nucleotide polymorphisms (SNPs) within ±100 kb of the UNC5C gene and a diagnosis of AD dementia, global cognitive decline, a pathologic diagnosis of AD, ?-amyloid load, neuritic plaque count, diffuse plaque count, paired helical filament tau density, neurofibrillary tangle count, and cerebral amyloid angiopathy (CAA) score. We also evaluated the relation of the CAA-associated variant and dorsolateral prefrontal cortex (DLPFC) UNC5C RNA expression. Secondary analyses were performed to examine the interaction of the CAA-associated SNP and known genetic risk factors of CAA as well as the association of the SNP with other cerebrovascular pathologies. RESULTS:A set of UNC5C SNPs tagged by rs28660566T was associated with a higher CAA score (p = 2.3 × 10-6): each additional rs28660566T allele was associated with a 0.60 point higher CAA score, which is equivalent to approximately 75% of the higher CAA score associated with each allele of APOE ?4. rs28660566T was weakly associated with lower UNC5C expression in the human DLPFC (p = 0.036). Moreover, rs28660566T had a synergistic interaction with APOE ?4 on their association with higher CAA severity (p = 0.027) and was associated with more severe arteriolosclerosis (p = 0.0065). CONCLUSIONS:Targeted analysis of the UNC5C region uncovered a set of SNPs associated with CAA.

SUBMITTER: Yang HS

PROVIDER: S-EPMC5515600 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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<i>UNC5C</i> variants are associated with cerebral amyloid angiopathy.

Yang Hyun-Sik HS White Charles C CC Chibnik Lori B LB Klein Hans-Ulrich HU Schneider Julie A JA Bennett David A DA De Jager Philip L PL

Neurology. Genetics 20170718 4

<h4>Objective</h4>To determine whether common genetic variants in <i>UNC5C</i>, a recently identified late-onset Alzheimer disease (LOAD) dementia susceptibility gene, are associated with AD susceptibility or AD-related clinical/pathologic phenotypes.<h4>Methods</h4>We used data from deceased individuals of European descent who participated in the Religious Orders Study or the Rush Memory and Aging Project (n = 1,288). We examined whether there were associations between single nucleotide polymor ...[more]

PMID: 28761931

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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: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.

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UNC5C variants are associated with cerebral amyloid angiopathy.

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<i>UNC5C</i> variants are associated with cerebral amyloid angiopathy.

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