Alzheimer?s disease (AD) is characterized by both, an accumulation of extracellular Amyloid-? (A?) plaques and intracellular tau tangles. The highest genetic risk factor for developing late-onset AD is Apolipoprotein E (ApoE) isoform ?4. In humans there are three ApoE isoforms: ApoE2, ApoE3, and ApoE4 that vary by one or two amino acids. ApoE4 impairs vesicular trafficking, resulting in synaptic dysfunction which occurs years before AD symptoms and pathology develop, suggesting a molecular mechanism for the accelerated disease onset in ApoE4 carriers. We have shown that the ApoE4-mediated synaptic defect is alleviated by acidifying the early endosomal pH with either a pharmacological block or genetic ablation of the Sodium/Hydrogen Exchanger (NHE) 6. This significant finding implicates NHE6 inhibition as a potential therapy for preventing AD in ApoE4 carriers. In order to move forward towards developing NHE6 inhibitor drugs, it is critical to evaluate how NHE6 inhibition alters AD pathology. Thus, we created an NHE6 knockout (NHE6-KO) mouse and bred it with an A? producing mouse model. Remarkably, A? plaque deposition is reduced by NHE6 depletion in vivo, further implicating NHE6 inhibition as a promising target for delaying AD. In this proposal, I will delineate the molecular mechanism behind the reduced plaque deposition that occurs with NHE6 ablation. Depletion of NHE6 in vivo results in an increase in glial activation, thus I hypothesize that the increased glial activation in NHE6-KO mice promotes the degradation of A?. Currently, the effects of early endosomal acidification on glial activation and A? clearance from the CNS has not been explored. The goal of this study is to determine if acidification of early endosomes in glial cells is detrimental or whether increased A? clearance is predominantly protective. In addition, it is crucial to investigate whether NHE6 inhibition in microglia causes an over-activated immune response. Thus, I will determine if NHE6-KO microglia induces a heightened immune response to bacterial or viral insult. Lastly, in this proposal I will investigate if NHE6-KO in microglia alone can reduce A? pathology and whether treatments with NHE inhibitors in the brain can enhance A? clearance in vivo using reverse microdialysis. Overall, the long-term goal for this grant is to evaluate the feasibility and efficacy of targeting NHE6 as a treatment for AD by using in vitro and in vivo methods.
Currently approximately 44 million people worldwide are diagnosed with Alzheimer?s or a related dementia. This proposal investigates a novel approach to prevent Alzheimer?s disease by increasing the acidity of the endolysosomal system and thereby promoting the removal of amyloid from the brain.
