Physiological role of naturally-occuring amyloid beta oligomers

Project: Research project

Project Details

Description

Surprisingly, evolution has retained in humans an amino acid sequence for the Aβ42 peptide that favors formation of large homo-oligomers. Self-assembling Aβ oligomers (AβOs) form rapidly in vitro, at nanomolar Aβ concentrations. The oligomer-promoting sequence also is present in certain other species (e.g., non-human primates; rabbit and chicken). Importantly, AβOs are found in AD brain tissue from humans and animal models, where they can comprise 12-24mers and larger species. This pathological buildup begins early in the disease, before plaques. These unusual homo-oligomeric molecules are neurologically disruptive in the adult CNS, and they are widely thought to instigate neural damage underlying AD dementia. The puzzle is what purpose is served by retaining this apparently dangerous capacity to form molecules that are potent CNS neurotoxins?
The puzzle of AβOs is addressed in the current project. It addresses the possibility that circumstances exist whereupon AβOs manifest a functional, physiological presence. In the long run, determining such circumstances is expected to give needed insight into the triggers and mechanisms of toxic AβO buildup in AD.
The working hypothesis to be tested is that AβOs have a transient, functional role during CNS development. Preliminary findings strongly support this hypothesis. Data from Western blots and immunohistochemistry indicate a presence of AβOs in the developing chick, a species whose Aβ sequence is the same as humans. AβOs appear to be selectively expressed by certain ganglion cells in the embryonic retina. Intriguingly, these same ganglion cells express tau phosphorylated at the Alzheimer’s serine-396 site. Nothing as yet has been learned about the function of the developmentally-regulated AβOs. It is feasible that the cellular impact of AβOs in development may be analogous to the pathological impact observed in adult. Developmental functions of AβOs could include such effects as inflammatory microglial activation, synaptic pruning and selective nerve cell death; when AβOs re-emerge pathologically in adults, these same effects are triggered, giving rise to AD. The Aims address the presence and function of AβOs in developing chick retina.
Aim 1 Determine the onset, peak expression, and disappearance pattern for specific AβO species during retina development.
Aim 2 Determine the influence that transient AβOs have on cellular development of retina, particularly with respect to microglia.
Results are expected to establish that Alzheimer’s-related AβOs serve a physiological role during development. Embryonic chick will be introduced as an exceptionally well-suited model for investigating the regulation of AβO expression and normal AβO function, including its relationship to tau. By understanding the normal biology of AβOs, it is expected that deeper insight into AβO pathobiology will be achieved. Significantly, it now appears that AβO pathobiology first found in AD likely will extend to retina degeneration in glaucoma, MD, and diabetes.
StatusActive
Effective start/end date8/15/185/31/20

Funding

  • National Institute of Aging (5R21AG060203-02)

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