Fig. 13. (A) Rationally designed multifunctional modulators targeting amyloid associated toxicity and neuroinflammation (blue: metal targeting moiety and green: l-dopa for antioxidant and anti-inflammatory activity in 4; blue: phenylacetamide moiety for neuroprotection and red: acetamide moiety for lipophilicity and stability in DAPPD; blue: DAPPD moiety and red: glucose moiety for BBB crossing in Glu-DAPPD; blue: triazacyclononane metal chelating moiety and red: 2-phenylbenzothiazole based Aβ targeting moiety in L1; blue: triazacyclononane metal chelating moiety, red: distyrylbenzene Aβ targeting moiety and green: vanillin based antioxidant moiety in LS-4; blue: 2,2′-bipyridine moiety for metal chelation and green: dopamine for antioxidant activity in 5). (B) Reduction of amyloid plaques (6E10 staining, scale bar 200 μm) and (C) microglial activation (Iba1, scale bar 50 μm) by DAPPD treatment in WT and APP/PSEN1 Tg mice. (D) Colocalisation of Aβ plaques with microglial cells in DAPPD treated cells (scale bar 10 μm). (E) Western blot analysis of NLRP3 and associated neuroinflammatory proteins and (F) its quantification in DAPPD treated WT and APP/PSEN1 mice brain samples. (B)– (F) Reproduced from ref. 245 with permission from PNAS, copyright 2019. (G) Immunofluorescence images of brain sections of 5xFAD mice treated with LS-4 stained for Aβ and quantification shows the reduction in Aβ load (scale bar 500 μm). (H) Reduction of tau aggregates by treatment with LS-4 as shown by AT8 staining and quantification (scale bar 125 μm). (I) LS-4 treatment ameliorates microglial activation as revealed by Iba1 immunofluorescence and its quantification (scale bar 125 μm). (G)–(I) Reproduced from ref. 248 with permission from the American Chemical Society, copyright 2021. (J) Structure of multifunctional modulator M3 (blue: DPA moiety for metal chelation, red: NMI for Aβ targeting and green: dopamine for antioxidant and anti-inflammatory activity). (K) Bio-AFM characterization of microglial activation and its reduction by M3 (scale bar 20 μm). (L) Western blot analysis of NF-κβ, TNFα and IL6 and its quantification in M3 treatment for its anti-neuroinflammatory effect. (K) and (L) Reproduced from ref. 225 with permission from the American Chemical Society, copyright 2022.