Evidence for a novel neuronal mechanism driving Alzheimer's disease, upstream of amyloid

Abstract

This perspective offers an alternative to the amyloid hypothesis in the etiology of Alzheimer's disease (AD). We review evidence for a novel signaling mechanism based on a little‐known peptide, T14. T14 could drive neurodegeneration as an aberrantly activated process of plasticity selective to interconnecting subcortical nuclei, the isodendritic core, where cell loss starts at the pre‐symptomatic stages of the disease. Each of these cell groups has the capacity to form T14, which can stimulate production of p‐Tau and β‐amyloid, suggestive of an upstream driver of neurodegeneration. Moreover, results in an animal AD model show that antagonism of T14 with a cyclated variant, NBP14, prevents formation of β‐amyloid, and restores cognitive function to that of wild‐type counterparts. Any diagnostic and/or therapeutic strategy based on T14‐NBP14 awaits validation in clinical trials. However, an understanding of this novel signaling system could bring much‐needed fresh insights into the progression of cell loss underlying AD.Highlights The possible primary mechanism of neurodegeneration upstream of amyloid. Primary involvement of selectively vulnerable subcortical nuclei, isodendritic core. Bioactive peptide T14 trophic in development but toxic in context of mature brain. Potential for early‐stage biomarker to detect Alzheimer's disease. Effective therapeutic halting neurodegeneration, validated already in 5XFAD mice.

Rodent Models of Alzheimer’s Disease: Past Misconceptions and Future Prospects

“…The salient part of AChE underlying its bioactivity in relation to AD is a 14mer peptide cleaved from its C-terminus, ‘T14’, generated from exon 6 of the AChE gene ( Figure 1 B). T14 is proposed to cause AD by recapitulating developmental mechanisms in the ageing brain, where events such as large increases in intracellular calcium or neuronal outgrowth are excitotoxic and thus cause cell death [ 218 , 277 ]. T14 is elevated in the human midbrain as early as the presymptomatic Braak stage II [ 217 , 218 , 278 ], and in vitro studies have shown it to induce excitotoxicity and reduce cell viability [ 279 ].…”