Table 2. Summary of experimental studies documenting the role of endosomal acid-base homeostasis in neurodegenerative diseases.
| Experimental system | Key findings | Reference |
|---|---|---|
| Post-mortem human brain tissue | Significantly lower NHE6 transcript and protein levels in AD brains relative to control | Prasad and Rao (2015b) |
| NHE6 downregulation in AD correlated with disease severity as determined by cognitive and pathological scores | ||
| NHE6 expression strongly correlated with synapse genes down regulated in AD | ||
| NHE6KO mice | Endolysosomal dysfunction, accumulation of unesterified cholesterol in endosomes and neurodegeneration | Stromme etal. (2011) |
| Endosomal hyperacidification, diminished neuronal arborization and synapse number | Ouyang et al. (2013) | |
| Lower brain weight and elevated Aβ levels in the brain | Prasad and Rao (2018a) | |
| Cell culture model | NHE6 blocks trafficking of APP from endosome to trans-Golgi network | Prasad and Rao (2015b) |
| Expression of NHE6 regulates physical approximation of substrate (APP) and enzyme (BACE1) | ||
| BACE1-mediated APP processing and Aβ production was elevated upon NHE6 depletion | ||
| Astrocytes | Endosomal hyperacidification and reduced surface levels of Aβ receptor LRP1 in ApoE4 astrocytes relative to ApoE3 astrocytes | Prasad and Rao (2018a) |
| Significantly lower NHE6 transcript and protein levels in ApoE4 astrocytes relative to ApoE3 astrocytes | ||
| Restoring NHE6 expression by lentiviral expression or HDACi treatment corrected surface LRP1 levels and defective Aβ clearance deficit in ApoE4 astrocytes | ||
| Neurons | Reduced surface levels of LRP8 in neurons treated with ApoE4 | Xian et al. (2018) |
| NHE6 lentiviral knockdown restores normal trafficking of LRP8 in the presence of ApoE4 | ||
| Non-selective NHE inhibitor EMD87580 restores normal trafficking of LRP8 in the presence of ApoE4 | ||
| PBMCs | Significantly lower NHE9 transcript levels in PBMCs in MS patients with an active disease course | Esposito et al. (2015) |
| NHE9 expression regulates polarization and differentiation of T cells | ||
| Proinflammatory IFNγ expression was elevated upon NHE9 depletion |
AD Alzheimer’s disease, MS multiple sclerosis, HDACi histone deacetylase inhibitor, PBMCs peripheral blood mononuclear cells, LRP1 LDL receptor related protein 1, LRP8 LDL receptor related protein 8, IFNγ interferon gamma