Red, theory; black, fact
Disclaimer
If you are a PD or AD patient or at risk and are seeking a cure outside the medical mainstream, this is not for you. This is written for researchers.
Inside Alzheimer’s and Parkinson’s
The commonest protein misfolding disease, Alzheimer disease, 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 four copper binding sites, including one on the amyloid beta sequence, and a zinc binding site.
What is the Power Source Driving Precipitation?
Inside the cell, copper is in the +1 oxidation state; outside, it is in the +2 oxidation state. Oxidation of the coordinated copper upon insertion of nascent APP into the plasma membrane could shift the coordination geometry of the copper ion from tetrahedral to square pyramidal, with 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 wound-up windup toy would be a familiar example of this. Multi-histidine binding sites such as those in APP can take up copper +1 ions even at the relatively low pH of the trans-Golgi network (6.0), where they would be located immediately prior to transport to the cell surface.
However, the idea that a coordination complex can couple mechanical force to a protein is questionable because at least one methylene, having two rotational degrees of freedom, always intervenes between a side-chain ligand and the protein backbone. Instead of bond angle changes, changes in copper-ligand bond strengths or coordination number upon oxidation of the copper centre may have to be considered as potentially leading to energy storage.
Role of the Power Source in the Healthy Brain
The local availability of this energy cache may be necessary to allow brief pre- and post-synaptic electrical coincidences to be rapidly captured as preliminary synaptic morphological changes. The growth factor-like domain of APP next to one of the copper binding sites, which may be positively charged due to the presence of chelated calcium ions, may be part of the electric field sensor. The acidic domain, which will be negatively charged, may be another part of the electric field sensor. Coulombic forces resulting from depolarization of the facing synaptic membrane will pull these two parts in opposite directions, thereby exerting a stretch on the E1 domain that pulls it open from the closed configuration to expose the two copper sites on it, which are then ready to support dimerization with APPs in the same state but anchored to the facing membrane. Coincidence detection would involve same-molecule binding of APP molecules on opposite sides of the synaptic cleft (Siddiqi and Craig, 2011). (Better known parts of the coincidence detecting system are the NMDA receptor and CAM kinase II).
How the Power Source Goes Wrong
Protein misfolding diseases of the brain may be powered by a short circuiting of the APP energy caches, or analogous caches in proteins subserving other functions. One of those other functions could be replenishing the supply of docked synaptic vesicles in response to a sudden increase in the average neuron firing rate. In that case, the relevant battery protein would be alpha synuclein, which is implicated in Parkinson disease. Local energy caches are also present in humanly engineered electronic circuits, where they are called decoupling capacitors.
Loss of Control of the Stored Energy
The secretases implicated in Alzheimer disease etiology would serve to degrade the APP molecules after their E1 domains have been opened, which I conjecture to be irreversible. Secretase beta action leads to the release of amyloid beta, the amyloid precursor, by secretase gamma. The stored energy remaining in the two APP copper sites immediately after E1 opening and cross-linking, or that in adjacent APP molecules, would drive the polymerization process that leads to amyloid formation by a mechanism that remains unclear.
Alternatively, the E2 domain and juxtamembrane segment of APP may function as an inchworm motor driven by cycles of synaptic release and reuptake of zinc and copper ions. The motor would be necessary to recycle the APP if the endocytosis pathway is not available, and would serve to extract half of the transmembrane segment so that it can be cleaved at the outer surface by gamma secretase to start the recycling process. To be able to exert traction on the transmembrane segment, the motor must brace itself on another synaptic component that has compressive strength, which may be the APP interaction partner for local instruction of permanent synaptic change. The energy invested by the inchworm motor would be that which subsequently drives amyloid beta precipitation in AD. Extracting half of the transmembrane segment would be energy-intensive because hydrophobic bonds are being broken and would create a new hydrophobic region on the future amyloid beta fragment in contact with cerebrospinal fluid: another state that stores energy. Hydrophobic re-bonding among such regions could directly drive polymerization and precipitation to insoluble amyloid.
The utility of newly created hydrophobic regions on proteins is easier to imagine for the central hydrophobic domain of alpha synuclein, the immediate effect being not precipitation but pulling two arbitrary ligands on different alpha synuclein molecules into closer proximity for a faster reaction between them. The trigger appears to be phosphorylation of alpha synuclein, not electric field change.
Closing a Fatal Positive Feedback Loop
By mischance, the soluble amyloid beta oligomers that form as intermediates along the amyloid-generating pathway may be able to spoof APP cross links (possibly by binding to the E1 domain and transitioning it to the open configuration in the absence of electric field change), thereby driving ectopic secretase beta activity and closing a feedback loop. This feedback would lead to an out-of-control production of amyloid beta that produces Alzheimer disease.
