Inflammatory signaling pathways in the treatment of Alzheimer's disease with inhibitors, natural products and metabolites (Review)

Abstract

The intricate nature of Alzheimer's disease (AD) pathogenesis poses a persistent obstacle to drug development. In recent times, neuroinflammation has emerged as a crucial pathogenic mechanism of AD, and the targeting of inflammation has become a viable approach for the prevention and management of AD. The present study conducted a comprehensive review of the literature between October 2012 and October 2022, identifying a total of 96 references, encompassing 91 distinct pharmaceuticals that have been investigated for their potential impact on AD by inhibiting neuroinflammation. Research has shown that pharmaceuticals have the potential to ameliorate AD by reducing neuroinflammation mainly through regulating inflammatory signaling pathways such as NF‑κB, MAPK, NLRP3, PPARs, STAT3, CREB, PI3K/Akt, Nrf2 and their respective signaling pathways. Among them, tanshinone IIA has been extensively studied for its anti‑inflammatory effects, which have shown significant pharmacological properties and can be applied clinically. Thus, it may hold promise as an effective drug for the treatment of AD. The present review elucidated the inflammatory signaling pathways of pharmaceuticals that have been investigated for their therapeutic efficacy in AD and elucidates their underlying mechanisms. This underscores the auspicious potential of pharmaceuticals in ameliorating AD by impeding neuroinflammation.

Keywords: Alzheimer's disease; inflammatory signaling pathways; inhibitor; neuroinflammation; treatment.

Figure 1

NF-κB signaling pathway and targets of inhibitors against neuroinflammation in AD. 1, rutin; 2, piperlongumine; 3, bee venom; 4, punicalagin; 5, tenuifolin; 6, D4 (a novel piperine derivative); 7, ethanol extract of Bupleurum falcatum; 8, macasiamenene F; 9, miconazole; 10, LD55; 11, the p65 binding domain of glucocorticoid-induced leucine zipper; 12, K284-6111; 13, epigallocatechin-3-gallate; 14, genistein; 15, oxysophoridine; 16, dihydromyricetin; 17, Gx-50; 18, protosappanin A; 19, icariside II; 20, ATP50-3; 21, DL0410; 22, tanshinone IIA; 23, APN; Aβ, amyloid β; LPS, lipopolysaccharide; D-gal, D-galactose; RAGE, receptor for advanced glycation end products; TLRs, Toll-like receptors; AMPK, adenosine 5′-monophosphate-activated protein kinase; MyD88, myeloid differentiation factor 88; TRAF6, TNF receptor associated factor 6; NEMO, NF-κB essential modulator; IKK, IκB kinase.

Figure 2

MAPK signaling pathway and targets of inhibitors against neuroinflammation in AD. AD, Alzheimer's disease; 1, MW01-2-069A-SRM; 2, MW181; 3, MMI-0100; 4, methanol extracts of Piper sarmentosum roots; 5, EGB761; 6, cryptolepine; 7, VB-037; 8, dexmedetomidine; 9, Hominis placenta; 10. BJe; 11, diammonium glycyrrhizinate; 12, tripterygium glycosides; 13, LX007; 14, pseudane-VII; 15, sorbinil and zopolrestat; 16, Artemisiae Iwayomogii Herba; 17, tectorigenin; 18, circumdatin D; 19, 1-O-acetylbritannilactone; 20, Ganoderma lucidum extract GLE; 21, Atractylodis Rhizoma Alba ethanolic extract; 22, ulmoidol; Aβ, amyloid β; LPS, lipopolysaccharide; TLRs, Toll-like receptors; MyD88, myeloid differentiation factor 88; IKK, IκB kinase; JNK, c-Jun NH2-terminal kinases; MK2, MAPK-activated protein kinase II; AP-1, activator protein 1.

Figure 3

NLRP3 signaling pathway and targets of inhibitors against neuroinflammation in AD. NLRP3, NOD-like receptor thermal protein domain associated protein 3; AD, Alzheimer's disease; 1, dapansutrile; 2, JC124; 3, MCC950; 4, ginkgolide B; 5, paeoniflorin; 6, A419259; 7, TAK-242; 8, CLI-095; 9, PEG-PEI/short interfering ROCK2; 10, pterostilbene; 11, LDS; 12, sulfa-4 and sulfa-22; Aβ, amyloid β; LPS, lipopolysaccharide; TLRs, Toll-like receptors; MyD88, myeloid differentiation factor 88.

Figure 4

PPAR, STAT3 and PI3K/Akt signaling pathways and targets of inhibitors against neuroinflammation in AD. PPAR, peroxisome proliferator-activated receptor; AD, Alzheimer's disease; 1, berberine; 2, rice bran extract; 3, telmisartan; 4, bis(ethylmaltolato)oxidovanadium; 5, platycodigenin; 6, (E)-2, 4-bis(p-hydroxyphenyl)-2-butenal; 7, (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol; 8, astaxanthin; 9, stattic; 10, protosappanin A; 11, curcumin; 12, Ent-Sauchinone; 13, sorafenib; 14, DHCR24 (3-β-hydroxysteroid-Δ-24-reductase); 15, sulforaphene; Aβ, amyloid β; LPS, lipopolysaccharide; IKK, IκB kinase; JAK2, Janus kinase; GSK-3β, glycogen synthase kinase-3β; PTEN, phosphate and tensin homolog deleted on chromosome 10.

Figure 5

Targeting inflammatory signaling pathways with drugs shows promise in AD treatment. By modulating various signaling pathways, drugs and inhibitors can effectively target microglia, neurons, and mice with AD. This targeted approach helps regulate inflammatory responses, promote neuronal survival, and restore functional recovery, ultimately alleviating symptoms of AD. AD, Alzheimer's disease; NLRP3, NOD-like receptor thermal protein domain associated protein 3; CREB, cyclic AMP response element binding; PPAR, Peroxisome proliferator-activated receptor; Nrf2, Nuclear factor erythroid 2-related factor 2.