## 4 Discussion and Conclusions  
Several interrelated mechanisms have been presented trying to explain the pathogenesis of [PERSON]'s disease, with the most prominent ones [31] being: (1) senile plaques which represent intracellular accumulations of Amyloid-\(\beta\) (A\(\beta\)) deposits; such deposits are accompanied by a formation of toxic oligomer aggregates and fibrils. (2) Neurofibrillary tangles (NFT) which represent the extracellular accumulation of hyperphosphorylated microtubule associated protein tau [31]. Toxic concentrations of A\(\beta\) trigger changes in tau and NFT formation. The related mechanisms of progressive neuronal damage are not well understood; still, it has been suggested that [31]: (i) aggregates of tau generate a stress response, and (ii) the microtubule stabilising function of tau is lost. Our results highlight the fundamental role of ion transport in maintaining cell membrane potential and cellular pH; indeed, [31]:  
* The metabolic syndrome (combining obesity, insulin resistance, arterial hypertension, low levels of HDL (High-Density Lipoprotein) and elevated triglycerides--principal risk factors for AD [34; 35]) is being understood as a consequence of a chronic state of inflammation paired with dyslipidemia, hyperinsulinemia, and dysglycemia [36];
* The deposits of A\(\beta\) trigger an inflammatory response through microglia and astrocytes [37; 38; 39], related to the aggregation of cleared peptide, and the stimulation of the mediator's secretion which generate the damage;
* Proteins can also be modified by nonenzymatic reactions with monosaccharides (glucose or fructose), due to the formation of hydroxyl radicals OH- which determine some reactions of rearrangement, dehydration, and condensation; this in turn generates heterogeneous derivatives named AGEs (Advanced Glycation End products), that play a fundamental role in the overproduction of intracellular ROS (Reactive oxygen species) [40] and the decrease in proteasomal activity, inflammatory response, cell insensitivity to insulin and induction of neuronal nitric oxide NO [40];
* Biometals (i.e., Cu, Zn, Fe) play a physiological role to maintain normal cellular processes, but they are also linked to AD due to their interaction with the amyloid substrates; their modulation with age may initiate AD signalling pathways and deregulate the metal ions homeostasis which in turn may intensify the disease [41];
* Insulin regulates glucose and lipid metabolism in the brain and neural development and activities [42] which represent a fundamental factor in key activities such as the process of learning and the development of memory. Insulin enters the brain via a saturated transport mechanism; insulin induces its intrinsic tyrosine kinase activity, which leads to its autophosphorylation [43]. Glucose metabolism performs a fundamental role in AD and it is possible to consider it related to the Metabolism Syndrome [31]. Indeed, the deficiency of insulin signalling conditionsthe PI3K/Akt (phosphoinositide 3-kinase/protein kinase B) pathway, thereby increasing APP processing, A\(\beta\) levels, and tau phosphorylation. Moreover, insulin inhibits IDE (Insulin-degrading enzyme) [31] damaging A\(\beta\) with a consequent increase of its neurotoxicity. Furthermore, mitochondrial dysfunction and oxidative stress [44] have been shown to play an important role in the early pathology of Alzheimer's Disease [44]. Minor changes in the mitochondrial membrane potential due to activity of potassium channels may play a crucial role, i.e., ROS synthesis, which plays an executive role in mitochondria upon channel activation or inhibition. Moreover, the functionality of mitochondrial large-conductance calcium-activated potassium channels allows us to understand the fundamental signalling role of calcium ions within the cell [45].