#82. Protein Batteries and Protein Misfolding Diseases [biochemistry]

Red, theory; black, fact

Last update: 03 Feb 2025

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 (growth factor-like domain) 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 heparan-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 discharged APP molecules. Let us suppose that secretase alpha acts rapidly to clear action-potential-discharged APP that did not make a cross link, and secretase beta acts slowly to clear cross links. Secretase gamma would complete the cleavage in both cases. Secretase alpha would have a recognition site for discharged APPs and secretase beta would have an allosteric recognition site for cross links. Beta secretase action is known to release amyloid beta, the battery part of APP. I postulate that the stored energy in amyloid beta drives the polymerization process that leads to amyloid formation. This energy release would involve a conformational change, consistent with the finding that amyloid protein is misfolded. The conformational change could expose hydrophobic residues on the surface of the protein, an energy-requiring step that could lead directly to precipitation due to hydrophobic bonding among the amyloid beta molecules.

By mischance, the soluble amyloid beta oligomers that form as intermediates along the amyloid-generating pathway are able to spoof APP cross links, thereby driving ectopic secretase beta activity and closing a feedback loop. This feedback leads to an out-of-control production of amyloid beta that produces Alzheimer’s disease.