Amyloid b-peptide (Ab), the major molecular component of the cerebral amyloid plaques, appears to play a central role in the neuropathology of Alzheimer's disease (AD). Compounds that prevent the formation of Ab aggregates or that selectively destroy these aggregates are attractive candidates for the development of therapeutic reagents for prevention and treatment of Alzheimer's disease. Also, compounds that interfere with the interactions of amyloid precursor protein (APP) with other factors that are involved in directing it into pathological pathway as well as those that are capable to prevent or destroy intraneuronal accumulations of Ab, are of great interest for developing therapeutic molecules for Alzheimer's disease. In this project we are proposing the possible immunological intervention for prevention and treatment of AD applying phage display technology for the construction of the first anti-Ab single chain fragment variable (scFv) antibody library and the selection of individual phage clones expressing Ab-specific scFv antibody, capable of preventing the aggregation of Ab or dissolving the preexisting aggregates, scFv phage display library enriched in anti-Ab antibodies will be constructed using the first strand cDNA synthesized from mRNA of spleen and lymph node cells isolated from mice immunized with Ab. The constructed library as well as a human scFv library will be used in bioselection procedure to isolate Ab-specific scFvs expressed on phage. The amino acid sequences of antibody complementarity-determinig regions (CDR) will be prepared and used as """"""""mini-antibodies"""""""". Evaluation of in vitro Ab aggregation and neurotoxicity in the presence of the selected compounds: scFv antibodies expressed on phage or in soluble form and """"""""mini-antibodies"""""""" will be performed. The most promising molecules selected in this project will be proposed for further evaluation in animal models to all researchers interested in these studies. If successful, these molecules could be of interest for passive immunization in humans, may be after modification with substances that would increase their blood-brain barrier permeability. ? ?
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| Gevorkian, Goar; Gonzalez-Noriega, Alfonso; Acero, Gonzalo et al. (2008) Amyloid-beta peptide binds to microtubule-associated protein 1B (MAP1B). Neurochem Int 52:1030-6 |
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