When a trophic process turns toxic: Alzheimer’s disease as an aberrant recapitulation of a developmental mechanism

Here we review the idea that Alzheimer’s disease (AD) results from aberrant activation of a normal developmental mechanism. This process operates in primarily vulnerable, subcortical nuclei with a distinguishing embryological provenance: the basal rather than the alar plate. All cells are dependent for growth on calcium influx yet these neurons retain a sensitivity to trophic factors into maturity. However, as the brain matures this action becomes detrimental such that the trophic process could turn toxic if triggered in adult brain, in retaliation to an initial insult. The signalling molecule driving this trophic-toxic mechanism is a 14mer peptide (T14) that acts on the alpha-7 receptor to enhance calcium entry, inducing excitotoxicity and proliferation of the receptor, perpetuating a feedforward cycle of neurodegeneration including production of beta-amyloid and p-tau. The T14 system has been previously unrecognised as a basic biological process, yet its pharmaceutical manipulation could have valuable clinical applications.