This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The goal of this pilot study is to understand the contribution the transmembrane glycoprotein, CD44, and its ligand, hyaluronan (HA), to the white matter changes that occur in Alzheimer's disease (AD). In addition to the well-characterized gray matter pathology in AD, there is also extensive white matter damage that contributes to AD patient morbidity. In particular, a high proportion of AD patients have white matter degeneration characterized by severe loss of myelin and oligodendrocyte apoptosis. Recent evidence indicates that amyloid-beta (A-beta) peptides are cytotoxic to oligodendrocytes, suggesting that A-beta peptides contribute to demyelination in AD patients. It is unclear, however, if A-beta peptides are the sole source of this cytotoxicity. Furthermore, as in other demyelinating lesions, it is unclear why neighboring unaffected oligodendrocytes or oligodendrocyte precursors fail to remyelinate affected axons. A recent study has shown that presenilin-dependent cleavage of the transmembrane region of CD44 results in the secretion of an A-beta-like peptide in a human embryonic kidney cell line. CD44 is dramatically overexpressed by reactive astrocytes in AD patient brains. Furthermore, we recently found that CD44 overexpression by astrocytes leads to the accumulation of HA, which in turn inhibits oligodendrocyte precursor maturation. We therefore propose to test the hypotheses that: (1) An A-beta-like peptide is generated by presenilin-dependent cleavage of CD44 expressed by reactive astrocytes, and this peptide is cytotoxic to nearby oligodendrocytes; and (2) That elevated CD44 correlates with both the accumulation of HA and increases in the numbers of oligodendrocyte precursors that fail to remyelinate damaged white matter in AD brains. Our hope is that these studies will provide substantial preliminary data for a larger grant (e.g., an NIH R01) that will focus on how CD44 and HA contribute to neurodegeneration and demyelination in AD.
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