The pattern of electromagnetic signals (PD) across the plasma membrane of brain cells is generated by the Na, K-ATPase system (Na-pump). The Na-pump runs, in turn, by the self-regulating 170 k Da cytosolic NaAF (endogenous activator), which is the “Sole Operator” of the Na-pump present universally in each cell. There are numerous reports suggesting that Alzheimer could be caused by an early neurodegeneration due to defective regulation or malfunction of the Na, K-ATPase system in brain. It appears that such malfunction of the Na-pump is caused by some defects in the auto-regulation of the NaAF molecule rather than defects in the Na, K-ATPase molecule itself. This is further explained as follows.

The Na, K-ATPase and the NaAF function together as single-unit, where the membrane-embedded Na, K-ATPase molecule acts as the ion-gates, and the cytosolic NaAF acts as the operator cum gate-keeper of the pumping system (RG publications). So, NaAF is the initiator of the newly generated electromagnetic signal in different brain areas each having characteristic αβ (area-specific) isoforms of the Na, K-ATPase system.Being the initiator of the Na, K-ATPase pump, NaAF is the mediator of electromagnetic thought-signals handled by area-specific isoforms of the Na-pump. Different areas of the brain containing different αβ-isoforms of the Na, K-ATPase have differential affinities towards Na, K, Ca and ATP. Hence, the nature and intensity of the area-specific thought-signals will be handled with different efficacy during transmission of the signal. Following depolarization those Na-pumps at the synaptic junction acting as provisional Ca-pumps (in altered states) to drive out excess Ca (> 10 µM), will also show differential activities towards Ca based on isoform (αβ)-nature, thus affecting the time for repolarization and signal flow.Also, the provisional Ca-pump pumping out excess Ca becomes temporarily independent of the NaAF, thus helping the Ca-pump to switch back to the original NaAF-dependent Na-pumping form to begin a new cycle cycle. Hence, NaAF can very well be a universal auto-regulatory Ca-sensor protein in the cell for maintaining homeostasis, and prevents neurons from lysis by swelling.  In addition, Ca plays a vital role in maintaining the intracellular level of the NaAF. Thus, the NaAF seems to regulate its intracellular level by regulating gene transcription via histone phosphorylation as well as mRNA translation controlled by microRNAs; and in both cases Ca plays a critical role.

 All those aspects controlling the brain Na-pumps in area-specific manner has been presented in an article, “Neurodegeneration due to the defective regulation of the Na, K-ATPase system by its cytosolic NaAF (170 k Da) activator: A Hypothesis” and posted in RG (DOI: 10.13140/2.1.1046.4327)