An Essential Role for Alzheimer's-Linked Amyloid Beta Oligomers in Neurodevelopment: Transient Expression of Multiple Proteoforms during Retina Histogenesis

Human amyloid beta peptide (A beta) is a brain catabolite that at nanomolar concentrations can form neurotoxic oligomers (A beta Os), which are known to accumulate in Alzheimer's disease. Because a predisposition to form neurotoxins seems surprising, we have investigated whether circumstances might exist where A beta O accumulation may in fact be beneficial. Our investigation focused on the embryonic chick retina, which expresses the same A beta as humans. Using conformation-selective antibodies, immunoblots, mass spectrometry, and fluorescence microscopy, we discovered that A beta Os are indeed present in the developing retina, where multiple proteoforms are expressed in a highly regulated cell-specific manner. The expression of the A beta O proteoforms was selectively associated with transiently expressed phosphorylated Tau (pTau) proteoforms that, like A beta Os, are linked to Alzheimer's disease (AD). To test whether the A beta Os were functional in development, embryos were cultured ex ovo and then injected intravitreally with either a beta-site APP-cleaving enzyme 1 (BACE-1) inhibitor or an A beta O-selective antibody to prematurely lower the levels of A beta Os. The consequence was disrupted histogenesis resulting in dysplasia resembling that seen in various retina pathologies. We suggest the hypothesis that embryonic A beta Os are a new type of short-lived peptidergic hormone with a role in neural development. Such a role could help explain why a peptide that manifests deleterious gain-of-function activity when it oligomerizes in the aging brain has been evolutionarily conserved.