Anti-Newt Collagen Type XII monoclonal antibody

Cerebral amyloid angiopathy (CAA), in which amyloid accumulates predominantly in the walls of arterioles and capillaries, is seen in most patients with Alzheimer disease (AD) and may contribute to compromise of blood-brain barrier (BBB) function seen in AD. We investigated the effects of CAA on BBB integrity by examining the expression of the endothelial marker CD31, basement membrane protein collagen IV (COL4), tight junction protein claudin-5, and fibrinogen, a marker of BBB leakage, by immunohistochemistry in the occipital cortex of autopsy brains with AD and capillary CAA (CAA type 1; n = 8), AD with noncapillary CAA (CAA type 2; n = 10), and AD without CAA (n = 7) compared with elderly controls (n = 10). Given the difference in pathogenesis of capillary and noncapillary CAA, we hypothesize that features of BBB breakdown are observed only in capillary CAA. We found decreased expression of CD31 in AD subjects with CAA types 1 and 2 compared with AD without CAA and an increase in COL4 in AD without CAA compared with controls. Furthermore, there was increased immunoreactivity for fibrinogen in AD with CAA type 1 compared with controls. These findings suggest that capillary CAA is associated with morphologic and possibly physiologic alterations of the neurovascular unit and increased BBB permeability in AD. (C) 2018 Elsevier Inc. All rights reserved.

BackgroundAlport syndrome is a clinically heterogeneous nephropathy characterized by severe symptomatology at kidney level due to ultrastructural lesions of the glomerular basement membrane (GBM) as consequence of mutations in COL4 genes. The disease has been linked to COL4A3/COL4A4/COL4A5 mutations, which impair GBM functionality and can be inherited in a dominant, recessive or X-linked transmission. Although a targeted Next Generation Sequencing approach has allowed identifying families with pathogenic mutations in more than one COL4 3-4-5 heterotrimer encoding genes, leading to conclude for a digenic pattern of inheritance, the role of non-collagen genes in digenic Alport syndrome has not yet been established.MethodsWe employed a whole-exome sequencing approach on three families in whom a digenic pattern of transmission could be suspected because of a likely biparental contribution or an unexplained phenotype in the proband.ResultsWe identified in the three probands hypomorphic LAMA5 mutations co-inherited with pathogenic COL4 4-5 chains mutations. Segregation analysis revealed that the combination of LAMA5/COL4 variants co-segregate with a fully penetrant phenotype in line with a digenic inheritance.In one of the three probands an hypomorphic variant in NPHS2 was also found, suggesting that role of other kidney disease related-genes as modifiers.ConclusionThese findings validate the impact of LAMA5 mutations in digenic ATS and highlight the role of extracellular matrix's genes, basement membrane, slit diaphragm and podocyte cytoskeleton in ATS. This underline the need for a more extensive panel approach in the presence of a digenic ATS, in order to better define clinical severity and recurrence risk for family members.