Immune-Mediated Mechanisms Underlying CNS abeta Clearance
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DESCRIPTION (provided by applicant): Abeta deposition and accumulation in the brain is hypothesized to trigger a complex pathological cascade leading to Alzheimer's diseases (AD). The current proposal will examine the efficacy of in situ CNS expression of anti-amyloid and anti-Abeta antibodies and single chain variable fragments (scFvs) with respect to attenuating AD-like pathologies present in APP mouse models. These studies will provide additional insight into proposed mechanisms relevant to the efficacy of anti-Abeta immunotherapy. By determining if selective targeting of fibrillar conformations of Abeta is more effective then targeting Abeta monomer, such studies may provide the scientific rationale for the development of novel forms of immunotherapy for AD. We will determine whether targeting of fibrillar Abeta amyloid as opposed to soluble monomeric Abeta is protective against development of AD-like pathologies in APP mouse models and whether antibodies targeting Abeta or Abeta amyloid are more effective then scFvs when expressed directly in the brain. We will also examine whether increased CNS expression of an efficacious anti-A¿ scFv enhances efficacy. Finally, we will use membrane tethered anti-Abeta and anti-amyloid scFvs to distinguish site or sties of action of anti-Abeta antibodies. By expressing membrane tethered scFvs in the brain we will determine if transport of scFvs out of the brain is required for efficacy. By expressing membrane tethered anti-Abeta or anti-amyloid scFvs in the liver we will attempt to definitively test the peripheral sink hypothesis (i.e., whether binding Abeta in the periphery is sufficient to enhance efflux from the brain and reduce Abeta deposition). We propose four specific aims that will utilize the power of recombinant adenoassociated viral vectors (rAAV) and the "somatic brain transgenic technology" to express recombinant antibodies/scFvs in the brain and periphery. Abeta deposition and accumulation in the brain is hypothesized to trigger a complex pathological cascade leading to Alzheimer's diseases (AD). A number of preclinical studies have shown that targeting Abeta using immunological approaches may be of benefit in humans with AD. Based on data we have generated in the past several years, we believe that a more optimal approach is to target fibrillar conformations of Abeta as opposed to Abeta monomer. We have developed a novel technology platform that enables us to use recombinant antibody fragments to selectivity target Abeta amyloid as opposed to Abeta itself. These studies may provide the scientific rationale for the development of novel forms of immunotherapy for AD.
