Surprisingly, evolution has retained an amino acid sequence for the human A?42 peptide that favors formation of large homo-oligomers. It is widely regarded that these unusual molecules are pathogenic. These oligomers accumulate in human and animal model brain tissue in an Alzheimer's disease-dependent manner. They have been shown experimentally to impact the CNS in a manner that causes memory dysfunction and recapitulates AD neuropathology (e.g., tau hyperphosphorylation, neuroinflammation, synapse loss, selective nerve cell death). Pathological A?O buildup begins early in the disease, before plaques, but it is not evident in healthy, non-demented adults. In vitro, toxic A?Os readily assemble from nanomolar concentrations of synthetic human A?. The same oligomer-forming sequence is found in certain animal species (e.g., nonhuman primates, rabbit, chicken, but not rodents). It is peculiar that these species have retained the apparently dangerous capacity to form molecules that instigate the neural damage leading to AD dementia. The current project addresses the possibility that circumstances exist whereupon A?Os manifest a functional, physiological presence. In the long- run, determining such circumstances is expected to give a significantly new perspective into the triggers and mechanisms of toxic A?O buildup in AD. The working hypothesis tested is that A?Os have a transient, functional role during CNS development, a possibility strongly supported by preliminary findings. Western blots and immunohistochemistry show the presence of A?Os in the developing chick, whose A? sequence is the same as humans. A?Os in embryonic retina are selectively expressed by ganglion cells, which, somewhat remarkably, likewise show a presence of tau phosphorylated at the AD serine-396 site. Nothing is known about the function of the developmentally-regulated A?Os, but it is feasible that the developmental impact may resemble the pathological impact observed in adult brain. Looked at another way, when A?Os re-emerge pathologically in adults, they impact brain tissue in a manner re-capitulating developmental functions. Developmental functions of A?Os thus might comprise, e.g., stimulation of tau hyperphosphorylation, microgliosis, synaptic pruning or selective nerve cell death.
The Aims test the hypothesis using developing chick retina for experimentation.
Aim 1 ? Determine the onset, peak expression and disappearance pattern for particular A?O species relative to AD-like tau hyperphosphorylation and microglial differentiation during retina development.
Aim 2 ? Determine the influence that transient A?Os exert on cellular development of retina, particularly with respect to microglia and tau hyperphosphorylation. Results are expected to establish that Alzheimer's-related A?Os serve a physiological role during development. Embryonic chick will be introduced as an exceptionally well-suited model for investigating the regulation of A?O expression and normal A?O function, including its relationship to tau and microglia. By achieving the first insights into normal A?O biology, it is expected that new and deeper insight into A?O pathobiology will be achieved.
Toxic A? oligomers (A?Os) are found in Alzheimer?s disease (AD) brain, where their pathological buildup is thought to instigate neural damage leading to dementia. It is peculiar that the capacity to form such neurologically disruptive molecules has been retained in humans and other species, suggesting the possibility that circumstances exist whereupon A?Os manifest a functional, physiological presence. Results here are expected to establish that Alzheimer's-related A?Os serve a physiological role during CNS development, and that by revealing the nature of normal A?O biology, the results will give a new and deeper insight into A?O pathobiology. Page 1 of 1
