Screening with in vivo phage display of peptide libraries has been employed as a new approach to identify specific molecular signatures present in the brains of transgenic mice that model Alzheimer's Disease (AD). Three peptides that recognize the hippocampus (the primary site of the disease) in two mouse models and not in the brains of normal littermates have been identified. So far, the lead peptide has been shown to bind to reactive astrocytes and endothelial cells in the neurovascular unit of AD hippocampus. This peptide also recognizes human AD-derived samples. The peptide bound to sections from an AD patient with sporadic AD to a much greater extent than to normal brain, and endothelial cells differentiated from human AD iPS cells also bound the peptide, whereas cells prepared similarly from a control individual did not. This application proposes to identify the molecular targets (receptors) for the three peptides. A candidate receptor has already been identified for the lead peptide. The receptors, because they distinguish AD from normal brain, may reveal new features of the pathogenesis of AD. They should also provide new opportunities for diagnostic and therapeutic targeting of AD. The approach proposed here significantly differs from the current state of the art in the field, as current approaches have generally focused on damage caused by accumulation of misfolded proteins such as amyloid plaques. In contrast, the first three peptides from the phage screens recognize alterations in the neurovascular unit and in extravascular neuronal tissue of AD hippocampus, and at least one of them does so prior to detectable plaque development.
We have identified three peptides that specifically recognize the hippocampus in a mouse model of Alzheimer's disease and in human AD-derived samples. We will identify the molecular targets (receptors) for the three peptides. These molecules, because they distinguish AD from normal brain, may reveal new features of the pathogenesis of AD that are different from the current approaches that have generally focused on amyloid plaques.