Therapeutic Potential of Cell-Type-Specific Upregulation of the NMD Pathway in Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the accumulation of amyloid plaques and neurofibrillary tangles. AD is rapidly growing, impacts millions worldwide, and is only expected to get worse in the coming years. Current research finds that neurodegenerative diseases, including AD, have selective neuronal vulnerability, meaning specific neurons are much more affected than others. In AD, this is the case for both cholinergic and glutamatergic neurons, with defects contributing to impaired cognition and behavior. Additionally, research has found that the upregulation of the nonsense-mediated mRNA decay (NMD) pathway has been shown to exert neuroprotective effects. Despite this understanding, current research in neurodegeneration has been entirely panneuronal, which may have unknown negative consequences or prove less effective than cell-type-specific approaches. Therefore, this article outlines the therapeutic impact of upregulating the NMD pathway in cell-type-specific cholinergic and glutamatergic neurons of AD, to showcase that cell-type-specific approaches to neurodegeneration may yield positive results compared to current panneuronal approaches. Ultimately, current research should establish whether a cell-type-specific approach to AD neurodegeneration outweighs the current panneuronal approach. If results are favorable, future research should expand this targeted avenue to other neurodegenerative diseases.