Type XV collagen occurs widely in the basement membrane zones of tissues, but its function is unknown. To understand the biological role of this protein, a null mutation in the Col15a1 gene was introduced into the germ line of mice. Despite the complete lack of type XV collagen, the mutant mice developed and reproduced normally, and they were indistinguishable from their wild-type littermates. However, Col15a1-deficient mice showed progressive histological changes characteristic for muscular diseases after 3 months of age, and they were more vulnerable than controls to exercise-induced muscle injury. Despite the antiangiogenic role of type XV collagen-derived endostatin, the development of the vasculature appeared normal in the null mice. Nevertheless, ultrastructural analyses revealed collapsed capillaries and endothelial cell degeneration in the heart and skeletal muscle. Furthermore, perfused hearts showed a diminished inotropic response, and exercise resulted in cardiac injury, changes that mimic early or mild heart disease. Thus, type XV collagen appears to function as a structural component needed to stabilize skeletal muscle cells and microvessels.T ype XV collagen belongs to the heterogeneous group of non-fibril-forming collagens and is thought to be a homotrimer consisting of three ␣1(XV) collagen chains (1). It is characterized by a central highly interrupted triple helical domain and large N-and C-terminal noncollagenous domains (2-4), and it has been shown to be a chondroitin sulfate proteoglycan (5). Type XV collagen mRNAs are expressed in many tissues, but the highest mRNA levels in the mouse can be detected in the heart and skeletal muscle (4). The protein is shown by immunostaining to have a widespread tissue distribution and has been localized mainly to the basement membrane zones, although it can also be found in the fibrillar collagen matrix of some tissues (6, 7). Its function is not known, however.In terms of primary structure, type XV collagen is highly homologous with type XVIII collagen, and together they form a distinct subgroup among the collagens (1, 3). They have thrombospondin-1 sequence homology in the N terminus, seven homologous collagenous domains, and highly homologous Cterminal noncollagenous domains. Type XVIII collagen is the precursor of endostatin, which has been shown to have a potent antiangiogenic effect (8), and the highest degree of homology between collagen types XV and XVIII involves the C-terminal endostatin sequence. The corresponding fragment in type XV collagen has also been shown to have antiangiogenic activity (9, 10).To understand the biological function and significance of type XV collagen, we generated a mouse strain lacking in ␣1(XV) collagen chains by site-specific Cre-loxP-mediated deletion in embryonic stem (ES) cells (11). The data suggest a structural role for type XV collagen in providing mechanical stability between cells and the extracellular matrix in skeletal muscle fibers and microvessels. Col15a1 deficiency leads to functional rather than struct...

Alzheimer's disease (AD) is a dementing neurodegenerative disorder without a cure. The abnormal parenchymal accumulation of b-amyloid (Ab) is associated with inflammatory reactions involving microglia and astrocytes. Increased levels of Ab and Ab deposition in the brain are thought to cause neuronal dysfunction and underlie dementia. Microglia, the brain resident cells of monocytic origin, have a potential ability to phagocytose Ab but they also react to Ab by increased production of proinflammatory toxic agents. Microglia originate from hemangioblastic mesoderm during early embryonic stages and from bone marrow (BM)-derived monocytic cells that home the brain throughout the neonatal stage of development. Recent studies indicate that BM or blood-derived monocytes are recruited to the diseased AD brain, associate with the Ab depositions, and are more efficient phagocytes of Ab compared with resident microglia. The clearance of Ab deposition by these cells has been recently under intensive investigation and can occur through several different mechanisms. Importantly, peripheral monocytic cells of patients with AD appear to be deficient in clearing Ab. This review will summarize the findings on the role of blood-derived cells in AD and discuss their therapeutic potential for treating patients suffering from this devastating disease. V

Although the Schwann cell basement membrane (BM) is required for normal Schwann cell terminal differentiation, the role of BMassociated collagens in peripheral nerve maturation is poorly understood. Collagen XV is a BM zone component strongly expressed in peripheral nerves, and we show that its absence in mice leads to loosely packed axons in C-fibers and polyaxonal myelination. The simultaneous lack of collagen XV and another peripheral nerve component affecting myelination, laminin ␣4, leads to severely impaired radial sorting and myelination, and the maturation of the nerve is permanently compromised, contrasting with the slow repair observed in Lama4 Ϫ/Ϫ single knock-out mice. Moreover, the Col15a1 Ϫ/Ϫ ;Lama4 Ϫ/Ϫ double knock-out (DKO) mice initially lack C-fibers and, even over 1 year of age have only a few, abnormal C-fibers. The Lama4 Ϫ/Ϫ knock-out results in motor and tactile sensory impairment, which is exacerbated by a simultaneous Col15a1 Ϫ/Ϫ knock-out, whereas sensitivity to heat-induced pain is increased in the DKO mice. Lack of collagen XV results in slower sensory nerve conduction, whereas the Lama4 Ϫ/Ϫ and DKO mice exhibit increased sensory nerve action potentials and decreased compound muscle action potentials; x-ray diffraction revealed less mature myelin in the sciatic nerves of the latter than in controls. Ultrastructural analyses revealed changes in the Schwann cell BM in all three mutants, ranging from severe (DKO) to nearly normal (Col15a1 Ϫ/Ϫ ). Collagen XV thus contributes to peripheral nerve maturation and C-fiber formation, and its simultaneous deletion from neural BM zones with laminin ␣4 leads to a DKO phenotype distinct from those of both single knock-outs.