Fig. 7. (A) Therapeutic approaches to target cholinergic and amyloid pathways. Therapeutics targeting (B) secretases, and (C) small molecules for Aβ aggregation (blue: quinoline moiety from clioquinol and red: phenolic moiety from EGCG in TGR86). (D) Peptides and peptidomimetics for Aβ aggregation (blue: sarcosine moiety and red: thymine in P5; blue: hybrid peptoid and red: GHK tripeptide in P6; blue: cyclic dipeptide kd in Akd^NMC). (E) Chemical structure of TGR63. (F) Dot blot assay of Aβ oligomer and fibril inhibition by TGR63 and its quantification in the absence (L1) and presence of TGR63 at two different molar ratios 1 : 1 (L2) and 1 : 5 (L3). (G) Binding of TGR63 with Aβ42 by MD simulation. (H) Reduction of the membrane toxicity of Aβ fibrils by TGR63 revealed by immunofluorescence with fibril antibodies. (I) Immunofluorescence images show the amelioration of amyloid load in the APP/PSEN1 Tg mice model with the treatment of TGR63 and its quantification. (J) Tracing of control and TGR63 treated mice in an open field test and (K) quantification of the total distance travelled by subjects. (L) Novel object recognition by control and treated animals as a measure of the discrimination index (DI). (M) TGR63 treatment rescue learning and memory deficits as revealed by improvement in the latency period, exploration and target crossing from the MWM test. (N) Schematic representation of fragments for Aβ vaccines, the target site of mAb and mechanism of action of mAb in Aβ reduction. (O) Therapeutics targeting metal ion toxicity (blue: metal binding moiety). (F)–(M) Reproduced from ref. 150 with permission from Wiley-VCH, copyright 2021.