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P4‐058: Identification of engulfment adaptor protein 1 as a novel Alzheimer's disease amyloid precursor protein interacting protein
Author(s) -
Hao Candy,
Chan Ho Yin,
Christopher Miller,
Lau KwokFai
Publication year - 2012
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.2012.05.1760
Subject(s) - amyloid precursor protein , signal transducing adaptor protein , microbiology and biotechnology , protein–protein interaction , immunoprecipitation , p3 peptide , biology , alzheimer's disease , biochemistry , signal transduction , gene , disease , medicine , pathology
pharmacologic blockade and genetic ablation of PLD1 alters APP processing in primary cortical neurons derived from these mice by analyzing relevant APP metabolites by Western blot and ELISA. Finally, we investigated whether genetic ablation of PLD1 affects cognitive functions in the context of the J20 mouse model using hippocampal-dependent memory tests. Results: Our results indicate that genetic ablation of PLD1 causes a significant reduction in total PLD activity as well as in the levels of PA in the forebrain. PLD1 ablation, unlike that of PLD2, causes a significant decrease in the levels of both soluble and insoluble Ab. Pharmacologic inhibition of PLD1 also decreases the secretion of Ab42 in cultured cells. Remarkably, PLD1 nullizygosity ameliorates synaptic defects and cognitive deficits observed in the J20 model of AD. Conclusions: We conclude that reducing the activity of PLD1 decreases the production of Ab; thus, PLD1 may be a novel therapeutic target to disrupt the molecular pathogenesis of AD. Overall, our recent studies suggest that blocking PLD1 or PLD2 may be beneficial in AD, although these two related lipases appear to affect distinct aspects of APP biology.