Red, theory; black, fact
The commonest protein misfolding disease, Alzheimer’s, features an accumulation of insoluble proteins as amyloid plaques that damage neurons and lead to dementia and death. The amyloid precipitates from a solution of amyloid beta protein, which forms by a two-step proteolysis of amyloid precursor protein (APP), an integral membrane protein of neurons.
APP is thought to play a role in the initial stage of synaptic plasticity and contains a copper binding site.
Oxidation of the coordinated copper upon insertion of nascent APP in the plasma membrane could shift the coordination geometry of the copper ion from planar-triangular to pyramidal, with huge changes in the preferred bond angles. If the coordinating protein cannot accommodate these changes without input of activation energy, the result would be a “protein battery”: a protein carrying a metastable “charge” of conformational strain energy. A set mousetrap would be a familiar example of this. The local availability of this energy cache may be necessary to allow brief pre-and-postsynaptic electrical coincidences to be rapidly captured as preliminary synaptic morphological changes. The calcium-binding site next to the copper binding site may be the electric field sensor. Coincidence detection would involve same-molecule binding of APP molecules on opposite sides of the synaptic cleft, triggered by propagation of unleashed conformational changes from the copper site into the main extracellular domain, called the heparin-binding domain. (Better known parts of the coincidence detecting system are the NMDA receptor and CAM kinase II).
I propose that protein misfolding diseases of the brain are powered by a short circuiting of the APP energy caches, or analogous caches in proteins subserving other functions.
The secretases implicated in Alzheimer’s etiology would serve to degrade the inevitable self-discharged APP molecules. This turnover process would sometimes generate amyloid beta fragments, which self-associate in hierarchical stages until precipitation as amyloid occurs. Still-soluble oligomers of amyloid beta may transiently bind to the intact, conditionally self-sticky APP, and the binding energy may supply the activation energy for the release of the stored conformational strain energy, thereby closing a pernicious positive feedback loop that leads to Alzheimer’s disease.
TO BE CONTINUED.
