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. 2019 Sep 19;10(43):10149-10158.
doi: 10.1039/c9sc03042e. eCollection 2019 Nov 21.

Alleviation of symptoms of Alzheimer's disease by diminishing Aβ neurotoxicity and neuroinflammation

Tao Yang  1 , Zhenzhu Zhu  1 , Enmao Yin  1 , Yanqing Wang  2 , Changli Zhang  3 , Hao Yuan  4 , Hongmei Zhang  1 , Suxing Jin  1 , Zijian Guo  4 , Xiaoyong Wang  1
Affiliations

Alleviation of symptoms of Alzheimer's disease by diminishing Aβ neurotoxicity and neuroinflammation

Tao Yang et al. Chem Sci. .

Abstract

Alzheimer's disease (AD) is one of the most prevailing neurodegenerative illnesses in the elderly. Accumulation of amyloid-β peptide (Aβ) and inflammation play critical roles in the pathogenesis and development of AD. Multi-target drugs may interdict the progress of AD through a synergistic mechanism. A neuromodulator, 2-((1H-benzo[d]imidazole-2-yl)methoxy)benzoic acid (BIBA), consisting of an Aβ-targeting group and a derivative of anti-inflammatory aspirin was designed as a potential anti-AD agent. BIBA exhibits a remarkable inhibitory effect on the self- and metal-induced Aβ aggregations and shows outstanding anti-inflammatory activity simultaneously. The neurotoxicity of Aβ aggregates is attenuated, and the production of pro-inflammatory cytokines (PICs), such as IL-6, IL-1β and TNF-α, in microglia stimulated by lipopolysaccharide (LPS) or Aβ is reduced. Owing to the synergy between the inhibition of Aβ oligomerization and downregulation of PICs, BIBA markedly prolongs the lifespan and relieves the Aβ-induced paralysis of Aβ-transgenic Caenorhabditis elegans, thus showing the potential to ameliorate the symptoms of AD through inhibiting Aβ neurotoxicity and deactivating microglia. These findings demonstrate that both Aβ aggregation and neuroinflammation are therapeutic targets for anti-AD drugs, and dual-functional agents that integrate anti-Aβ and anti-inflammatory capabilities have great advantages over the traditional single-target agents for AD treatment.

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Figures

Fig. 1
Fig. 1. Construction of BIBA.
Fig. 2
Fig. 2. Prevention of self- or metal-induced Aβ40 aggregation by BIBA. (A) CD spectra, (B) TEM, and (C) Western blot of Aβ40 without or with metal ions and BIBA, and ESI-MS spectra of Aβ40 with (D) Zn2+ or (E) Cu2+ in the presence of BIBA ([Aβ] = [Zn2+/Cu2+] = 10 μM and [BIBA] = 20 μM).
Fig. 3
Fig. 3. (A) Viability of N2a cells in the presence of Aβ42 without or with metal ions and BIBA after incubation for 24 h determined by the MTT assay, and (B) expression of apoptosis-related proteins in N2a cells stimulated with Aβ42 aggregates in the presence and absence of BIBA for 24 h detected by the Western blot (n = 3; **P < 0.001 and *P < 0.01; [Aβ] = [Zn2+/Cu2+] = 10 μM, and [BIBA] = 20 μM).
Fig. 4
Fig. 4. (A) Different motion modes of CL4176, (B) effects of drugs on the paralysis of CL802 or CL4176 worms at 25 °C, (C) survival curves of CL4176 worms after treatment with drugs at 15 °C, (D) mean lifespan of CL4176 worms after drug treatment calculated by using GraphPad Prism 7, (E) photos of CL4176 worms after drug treatment at 25 °C for 48 h and then stained with ThS, (F) Western blot of Aβ species and (G) inflammatory mediators in CL4176 worms treated with drugs at 25 °C for 48 h, and (H) quantitative analysis of inflammatory cytokines by using ImageJ and GraphPad Prism 7. All results are presented as mean ± SEM (n = 2); *p < 0.0001 ([aspirin] = [BIBA] = 20 μM).
Fig. 5
Fig. 5. Inhibition effect of BIBA on PICs. (A) Western blot and (B) quantitative analysis of PICs and mediators in BV-2 cells stimulated by LPS or Aβ42 in the presence or absence of BIBA at 37 °C for 12 h, and (C) immunofluorescence images showing the expression of CD86 in Aβ-exposed BV2 microglia in the presence or absence of BIBA. The results are presented as mean ± SEM (n = 2); ****P < 0.0001, ***P < 0.001, **P < 0.01 and *P < 0.1 ([LPS] = 1 μg mL–1, [Aβ42] = 10 μM, and [BIBA] = 20 μM).
Fig. 6
Fig. 6. Reduction of Aβ expression and microglia overactivation. Histochemical analyses of Aβ deposition (green) and Iba-1 (red) in WT and APP/PS1 mice brain after treatment with vehicle, aspirin (1.4 mg kg–1) and BIBA (2 mg kg–1), respectively, every 3 days for 3 months.
Fig. 7
Fig. 7. Calculated surroundings of BIBA–Aβ40 monomers (A and B) and fibrils (C and D).
Fig. 8
Fig. 8. Schematic diagram showing the mechanism of BIBA-mediated protection of neurons in the AD brain.
See this image and copyright information in PMC

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