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The APP Interactome: Identifying Targets in Alzheimer's Disease
Author(s) -
Glucksman Marc,
Philibert Keith,
Marr Robert,
Norstrom Eric
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.726.9
Subject(s) - interactome , amyloid precursor protein , proteome , computational biology , biology , amyloid (mycology) , neprilysin , in vivo , microbiology and biotechnology , chemistry , biochemistry , neuroscience , alzheimer's disease , disease , medicine , enzyme , gene , genetics , botany
Alzheimer's disease (AD) is a horrific neurodegenerative disorder affecting the elderly with progressive mental decline and profound effects on memory. Accumulating evidence indicates that the failure to clear the 40‐42 a.a. Aß peptides from the brain is a primary step in the pathology of sporadic AD. We utilized proteomic approaches involving isolation of physiologically relevant macromolecular complexes in vivo of proteins interacting with Amyloid Precursor Protein (APP) or the carboxy terminally located Amyloid IntraCellular Domain (AICD). After in vivo tandem affinity purification in cell culture models, downstream biophysical characterization and mass spectrometry identified individual interactors currently being validated. A new peptidase activity exhibited by metalloendopeptidase, EC 3.4.24.15 (EP24.15) was identified with the ability to degrade Aß at 3 sites and is different from identified activities of neprilysin 1/2 and insulysin. Transthyretin, a carrier protein transporting thyroid hormones was identified and interactions with Aß were quantified in the µM range with ramifications to inhibit Aß multimer formation. Validation has commenced with the target NEEP21, a neuronally expressed single‐pass transmembrane protein was expressed in lentiviral transduced cells and animals to examine the effects on Aß production. Taken together this data suggests that explicating interactions with APP and AICD can have effects on neurotoxic products and may aid in developing effective pharmacological approaches for people afflicted by AD. Support: RFUMS/DePaul Pilot program and NIH OD010662 (MJG) to the Midwest Proteome Center.