**2.4 Metal chelation therapy, a potential treatment for Alzheimer's disease**

Based on the thesis that AD pathology relates to the interplay between metal ions and *Aβ*, treatments for AD have been proposed established on this characteristic. Metal chelation therapy has been raised as a method to agitate metal- *Aβ* interactions to treat AD in a lot of research [27]. Metal chelation therapy is initiated by injection of chelators (chelating agents) into the bloodstream which bind to the targeted metals and excrete them [34].

Studies show that metal chelating agents must satisfy the following conditions to manipulate as prospective treatments for AD.

1.Low molecular weight


4.Low toxicity

5.Low possibility of side effects

Metal chelators content with above properties will successfully affix to aimed metal ions associated with *Aβ*, engendering their break-up and removal [27].

Among the various chelator drugs, only a few are suitable for AD; drugs that fulfill the properties stated above. The common chelator drugs adopted for AD treatments that have shown favorable results include desferrioxamine (DFO), bathophenanthroline, bathocuproine (BC), trientine, penincillamine, bis (thiosemicarbazone), tetrathiomolybdate (TTM) [35–37].

In one clinical trial in 48 patients with AD, DFO has shown its positive effects. Using trace-metal analysis, the research team confirmed that DFO decreased the aluminum level in neocortical brains of AD patients dosed with DFO;125 mg per injection, twice a day, five days a week [38]. Although it showed outcomes regarding aluminum, one research insisted that, considering the affinity DFO has for iron, the result might have also been due to the elimination of iron [39]. In addition to iron, DFO also shows binding affinity towards copper [40].

Penincillamine, bathophenanthroline, bathocuproine (BC), and trientine have also been proven to be effective copper chelators. In one research test, these agents showed interaction with *Cu*- *Aβ* couple, deleting copper and improving *Aβ* solubility. Furthermore, BC has been proved to be the most efficacious, showing constant results across the broad range of AD brain tissue samples [37].

It has been suggested that the bis(thiosemicarbazone) compounds can regulate the concentration of copper in *Aβ* as well [41]. In one study, chemical compounds of the bis (thiosemicarbazone) metal complex family have shown successful treatment for animal models with AD [42]. Similar results have been noticed in another study using APP/PS1 transgenic AD mice model as well. Bis(thiosemicarbazone) enhanced the soluble *Aβ* level by deleting copper and led to the restoration of cognitive activity [43].

The effect of tetrathiomolybdate (TTM) as a copper chelator has been demonstrated as well. In one experiment, TTM was applied to Tg2576 transgenic mice model for five months. Positive effects were derived, showing that TTM lowered both the level of *Aβ* and *Aβ* plaques present in the brain [44].

#### **2.5 Challenges of metal chelation therapy**

Although the above-stated metal chelating agents have shown positive effects in reducing *Aβ* levels in AD patients, there are still challenges surrounding the metal chelation therapy.

First, in addition to the originally aimed effects, metal chelating agents can induce undesirable outcomes as well. One study revealed that the application of divalent chelators, such as *Cu*, *Fe* and *Zn*, to severe AD patients lessened the requisite divalent metals that were already in their appropriate levels, as well as the targeted metal ions. Accordingly, the depletion of essential metals aggravated rather than treated AD pathology [45].

Furthermore, as stated in *Metal Chelation Therapy, a Potential Treatment for Alzheimer's Disease*, metal chelating agents have been proved to lower*Aβ* level through solubilization. However, it is still rather controversial whether metal chelators can not only *solubilize* but *reverse* the *Aβ* plaques to any forms of intermediates such as monomers, oligomers, protofibrils, short fibrils, or extended fibrils [27, 45].

Finally, there are remaining questions concerning the efficacy of certain metal chelating agents. For instance, clioquinol (CQ), a*Cu* - *Zn* chelator capable of agitating *Aβ* aggregation has been used in numerous clinical trials. However, the clinical and experimental results show that the effectiveness of CQ is yet contentious [45, 46]. In one experiment, the utilization of CQ perturbed *Cu* and *Zn* homeostasis which elevated metal ion concentrations, which is contradictory to the predicted results. CQ also showed side effects, arising astrogliosis, spongiosis, and brain edema to the mice model [47].

For further development of metal chelation therapy, such disadvantages should be improved.

### **3. Conclusion**

*Aβ* and amyloid plaques are determining symbols of AD. Metal ions, especially copper and iron, interact with *Aβ* in AD patient's brain which generates ROS, such as superoxide anion, hydrogen peroxide, and hydroxyl radical. This process promotes the aggregation *Aβ* and increases the toxicity of *Aβ* plaques. ROS induces damages to both *Aβ* itself and the surrounding molecules leading to protein, lipid, DNA, and RNA impairment. Metal chelation therapy has been proposed as method to agitate metal-*Aβ* interactions for AD treatment. Metal chelators injected into the bloodstream will target metals associated with *Aβ* and eliminate them, cutting off the activity of causative substances. The metal chelating agents that have shown positive effects towards AD so far include desferrioxamine (DFO), bathophenanthroline, bathocuproine (BC), bis(thiosemicarbazone), tetrathiomolybdate (TTM), trientine, and penicillamine. However, there are ongoing challenges facing the metal chelation therapy. The remaining questions regarding the efficacy of chelating agents and the precise mechanism of chelation therapy should be solved.
