Prevention of Alzheimer's Disease Through NHE6 Depletion

Currently, 1 in 9 people over the age of 65 are living with Alzheimer's disease (AD). The highest genetic risk factor for AD is Apolipoprotein E isoform E4 (ApoE4), which accounts for 40-65% of AD patients. AD is characterized by brain atrophy, synaptic dysfunction, and the accumulation of amyloid and tau proteins. These AD phenotypes are exacerbated in the presence of ApoE4, yet the molecular mechanism remains unknown. To develop therapies for AD, it is of the utmost importance to understand the basic molecular and cellular mechanism by which ApoE4 accelerates AD onset and progression. We have previously identified that ApoE4 halts early endosomal recycling, which subsequently causes synaptic dysfunction and impaired learning and memory. We propose a novel approach for rescuing the ApoE4-mediated impairment in endosomal recycling and synaptic dysfunction by lowering the pH of the early endosomes through inhibition or depletion of the early endosomal proton leak channel Na+/H+ Exchanger 6 (NHE6). The long-term goal of our research is to develop a treatment strategy for ApoE4 carriers during the 10- to 15-year period preceding the onset of clinical symptoms. During this period, patients with preclinical AD start accumulating Abeta plaques in the neocortex. The first aim of my thesis project was to investigate how NHE6 depletion affects Abeta pathology. The second aim was to evaluate any untoward side effects such as neuroinflammation or neuronal loss caused by the complete genetic removal of NHE6. For the last portion of my thesis project, I investigated a translational approach to target NHE6 as a therapeutic strategy by using anti-sense oligonucleotides against NHE6. Overall, the goal of my thesis is to determine if NHE6 is a rational target for delaying and/or preventing AD. The findings from my thesis have provided some underlying mechanisms of how NHE6 reduces Abeta plaque load but also have opened new doors on other avenues we need to explore before moving from preclinical to clinical trials.