Abstract Body

ApoE4 is the most prevalent and clinically most important risk factor for late-onset Alzheimer’s disease (AD). Three major ApoE isoforms exist in humans which differ by the presence of a positively charged arginine or a neutral cysteine at residues 112 and 158, respectively. The main biophysical difference between these different ApoE isoforms therefore is their net charge, and disease risk correlates with their isoelectric point (IEP). The higher the IEP, the greater the disease risk. The IEP of ApoE4 closely matches the pH of the early endosomes, which undergo swelling and impaired trafficking upon endocytosis of ApoE4. We showed previously that this trafficking defect can be completely abolished by pharmacologically inhibiting or genetically reducing NHE6, the main proton leak channel specifically in early endosomes. We now show that genetic disruption of NHE6 prevents amyloid accumulation in a humanized APP knocking mouse model, abolishes all functional differences between ApoE isoforms and restores synaptic dysfunction in humanized ApoE4 knockin mice. These findings reveal NHE6 as a novel rational therapeutic target for the prevention of late-onset AD.