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P4–320: Development of novel disease–modifying small peptides that cause a reduction of brain amyloid plaque load and improved memory in a transgenic mouse model of Alzheimer's disease
Author(s) -
Snow Alan D.,
Cummings Joel A.,
Lake Thomas P.,
Rockenstein Edward,
Masliah Eliezer,
Castillo Gerardo M.
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.2061
Subject(s) - thioflavin , genetically modified mouse , amyloid (mycology) , fibril , peptide , amyloid beta , senile plaques , alzheimer's disease , amyloidosis , laminin , chemistry , morris water navigation task , amyloid precursor protein , biochemistry , transgene , microbiology and biotechnology , biology , hippocampus , medicine , pathology , neuroscience , disease , extracellular matrix , gene
Our previous work identified a region within the globular domain of laminin that binds effectively to the beta-amyloid protein of Alzheimer’s disease (AD), inhibits beta-amyloid protein fibril formation, and disrupts pre-formed beta-amyloid protein fibrils. Screening of over 300 synthetic peptides (12and 13-mers) derived from globular domain regions of various laminin A chains resulted in the identification of 19 peptides with marked beta-amyloid protein-fibril disrupting activity. Novel 6-9 mer peptide analogs were designed that were derived from their parent 12-13 mer peptide sequences, and confirmed to maintain beta-amyloid fibril disrupting ability by a number of different in vitro screening assays. In the present study the effects of four of the top peptides on potential reduction of brain amyloid load and improved memory was assessed in a transgenic model of AD. Groups of 6-6.5month old APP mice (containing the London and Swedish mutations) were injected daily i.p. (at 50mg/kg/day) for 90 days with either saline, or four different novel 6-9mer peptides (as described above). The results demonstrated that two of these novel peptides significantly reduced fibrillar beta-amyloid protein load in brain of APP mice (as assessed by image analysis quantitation of Thioflavin S fluorescence and Congo red staining) by 38-63%, and one of these peptides also caused a marked and significant improvement (by 52%) in hippocampus dependent memory (i.e. spatial acquisition) as determined by Morris water maze testing. These results suggest that small novel peptides show promise for the development of new disease-modifying therapeutics for the prevention and treatment of AD and related disorders.