Abstract
Currently, there are very limited pharmaceutical interventions for Alzheimer’s disease (AD) to alleviate the amyloid burden implicated in the pathophysiology of the disease. Alzheimer’s disease is characterized immunohistologically by the accumulation of senile plaques in the brain with afflicted patients progressively losing short-term memory and, ultimately, cognition. Although significant improvements in clinical diagnosis and care for AD patients have been made, effective treatments for this devastating disease remain elusive. A key component of the amyloid burden of AD comes from accumulation of the amyloid-beta (Aβ) peptide which comes from processing of the amyloid precursor protein (APP) by enzymes termed secretases, leading to production of these toxic Aβ peptides of 40–42 amino acids. New therapeutic approaches for reducing Aβ are warranted after the most logical avenues of inhibiting secretase activity appear less than optimal in ameliorating the progression of AD.Novel therapeutics may be gleaned from proteomics biomarker initiatives to yield detailed molecular interactions of enzymes and their potential substrates. Explicating the APPome by deciphering protein complexes forming in cells is a complementary approach to unveil novel molecular interactions with the amyloidogenic peptide precursor to both understand the biology and develop potential upstream drug targets. Utilizing these strategies we have identified EC 3.4.24.15 (EP24.15), a zinc metalloprotease related to neprilysin (NEP), with the ability to catabolize Aβ 1–42 by examining first potential in silico docking and then verification by mass spectrometry. In addition, a hormone carrier protein, transthyreitin (TTR), was identified and with its abundance in cerebrospinal fluid (CSF), found to clear Aβ by inhibiting formation of oligomeric forms of Aβ peptide. The confluence of complementary strategies may allow new therapeutic avenues as well as biomarkers for AD that will aid in diagnosis, prognosis and treatment.
Highlights
Alzheimer’s disease is a terrible neurodegenerative disorder affecting the elderly resulting in progressive mental decline with profound effects on memory
Literature was somewhat conflicting explicating the role of the EP24.15 metalloenzyme in the etiology of Alzheimer’s disease (AD). This enzyme was originally erroneously thought to be the β-secretase activity initiating the processing of the amyloid precursor protein (APP) into Aβ (Papastoitsis et al, 1994) prior to the discovery of the beta amyloid cleaving enzyme1 (BACE-1)
NEUROPEPTIDE PROCESSING ENZYME EP24.15 Utilizing the model of the structure of the empty form of EP24.15 (Research Collaboratory for Structural Bioinformatics—Protein Data Bank, entry 1S4B; Ray et al, 2004), Aβ 1–40 or Aβ 1– 42 could potentially interact in silico upon “closing” around the substrate with subsequently cleaved peptide products that can be subjected to amino and carboxypeptidases for further degradation into smaller peptide fragments
Summary
Alzheimer’s disease is a terrible neurodegenerative disorder affecting the elderly resulting in progressive mental decline with profound effects on memory. Many of the most potent gene polymorphisms that confer risk for AD affect clearance of Aβ (Bu, 2009; Kim et al, 2013; Reitz et al, 2013). Mice deficient in ECE-1 or NEP show elevated levels of the Aβ peptide (Iwata et al, 2001; Eckman et al, 2003, 2006; Madani et al, 2006; Rodriguiz et al, 2008; Walther et al, 2009), and some polymorphisms in these genes have been associated with risk of developing AD (Marr and Spencer, 2010; Pacheco-Quinto et al, 2013). Neprilysin-2 (NEP2), which has been demonstrated in vivo to control Aβ levels by cleaving Aβ between amino acids Val and Leu similar to Frontiers in Aging Neuroscience www.frontiersin.org
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
