My work has primarily dealt with molecular mechanisms of neurodegeneration (mainly Alzheimer’s disease) with an emphasis on identifying molecular markers and therapies. Deficiencies in clearance of the amyloid-beta (Ab) peptide are thought to contribute to the development of Alzheimer’s disease (Marr et al. 2014. PMID:25165447)(http://journal.frontiersin.org/Journal/10.3389/fnagi.2014.00310/full). The endopeptidase neprilysin (Nep) has been shown to be a key enzyme regulating Aß (Marr et al. 2003. PMID:12657655). However, evidence suggests the existence of other proteases that contribute to the clearing of Aß (Marr et al. 2010. PMID:20088804). Neprilysin-2 (Nep2) is the closest known homolog to Nep and is expressed in the brain; therefore, Nep2 is a good candidate for an enzyme that cooperates with Nep to control cerebral Aß levels. Our group has identified a new property for the Nep2 enzyme, in that it can degrade the Ab peptide in humans (Huang et al. 2008. PMID:18571334). We also found that Nep2 functions in vivo to significantly reduce Ab peptide levels in the rodent brain (Hanson et al. 2010. PMID:20941644; Hafez et al. 2011. PMID:21224067). Finally, we showed that the expression and activity of Nep2 is altered in association with preclinical Alzheimer’s disease (Huang et al. 2012. PMID:22008264). This finding suggests that Nep2 quantitation might serve as an early predictor of risk for developing the disease. My work on therapeutic applications to Alzheimer’s disease also extends to the use of antisense technology to specifically target genes linked to disease pathogenesis. Finally, in collaboration with DePaul University, I am also working on the therapeutic application of gene-manipulation of novel amyloid precursor protein (APP) interacting proteins (Philibert et al. 2014. PMID:25346686) for Alzheimer’s disease.
In addition to my work as part of the department of Neuroscience, I am also a center investigator at the Center for Stem Cell and Regenerative Medicine here at RFUMS. My work with the center includes the investigation of the cross-talk between neurogenic pathways and neurodegeneration. Related to this, we have reported that gene transfer of the pro-neurogenic F-spondin gene reduced Alzheimer’s-like pathology in mice (Hafez et al. 2012. PMID:22863679). Our interests also extend to the use of gene transfer vectors to “reprogram” cells in vitro and in vivo to produce induced neurons for disease modeling and therapeutic applications. Related to this we have used retroviral vectors for the manipulation of endogenous progenitor cell fate in the brain (Klempin et al. 2012. PMID:22162276). Lastly, this work has implications for the study and treatment of traumatic brain injury which we are pursuing in collaboration with investigators at DePaul University.