Why do people with the APOE4 variant of APOE have a much greater risk of Alzheimer's disease? Past work has focused on its role in accelerating amyloid-β accumulation by disrupting recycling mechanisms in some way. Evidence is provided here for the relevant mechanisms to trace back to the acidity of the environment within parts of the cellular recycling system which APOE operates. APOE4 is more prone to dysfunction in that environment than is the case for other APOE variants. Manipulating the regulators of acidicity may thus enable Alzheimer's disease to be slowed down at its very earliest stage - though the size of that effect in patients is a question mark. It seems plausible that it will have little effect on people with variants other than APOE4, for example.
ApoE is a lipid and cholesterol carrying protein that is primarily produced by the liver and is responsible for plasma lipid homeostasis. It occurs in three major isoforms in humans known as ApoE2, ApoE3 and ApoE4, with ApoE3 being the most frequent allele (~77% homozygosity) followed by ApoE4 (~15-20% allele frequency) which is present in more than 50% of late onset Alzheimer's disease patients. The effect of ApoE4 on amyloid-β (Aβ) accumulation through impaired Aβ turnover, increased aggregation, and thus plaque formation is allele dosage-dependent and this can partly explain its effect on the earlier age of disease onset. However, ApoE4 can independently impair synapse function and Ca2+ homeostasis by disrupting the endocytic transport and recycling of synaptic ApoE receptors and the excitatory AMPA and NMDA type glutamate receptors that are regulated by those ApoE receptors and that are consequently trapped with them in the same vesicles.
The molecular basis by which ApoE4 causes the disruption of normal endosomal vesicle transport and recycling is most likely the result of its propensity to unfold and assume a 'molten-globule' conformation upon entering an acidic environment. ApoE4 differs from ApoE3 by a single amino acid, which alters its isoelectric point to coincide with the pH of ~6.5 that is present in the early endosome. We hypothesized that this isoelectric charge neutralization would make ApoE4 prone to aggregation, which could be the molecular basis for the ApoE4-induced and gene dosage-dependent recycling defect.
pH in the early endosome is maintained by the opposing functions of the proton pump, which decreases vesicular pH, and the Na+/H+ exchanger NHE6, which increases it. Here, we have investigated the role of NHE6 inhibition as a means of lowering endosomal pH, away from the isoelectric point of ApoE4. We found that this simple pharmacological intervention releases the endosomal ApoE4 block, restores the normal trafficking of ApoE receptors and glutamate receptors in neurons and corrects the functional defects in vitro and in vivo. Together these findings suggest that drugs that make vesicles in neurons more acidic may have the potential to help prevent individuals that carry the ApoE4 protein from developing Alzheimer's disease. Current drugs that target NHE6 also affect other molecules, which can often lead to side effects. A next step will be to develop tailor-made, small molecule drugs that can enter the brain efficiently and selectively block NHE6.