<p>Chlorogenic Acid Alleviates Aβ_25-35-Induced Autophagy and Cognitive Impairment via the mTOR/TFEB Signaling Pathway</p>

Abstract

Chlorogenic acid (CGA), a phenolic acid isolated from fruits and vegetables, has been established to have neuroprotective properties in relation to Alzheimer's disease (AD). However, the precise mechanism by which CGA prevents cognitive deficits in AD has not been well studied. This study aimed to explore the potential molecular mechanism of CGA action using an Aβ 25-35-induced SH-SY5Y neuron injury and cogxnitive deficits model in APP/PS1 mice. Methods: Three-month-old male APP/PS1 double transgenic mice and a human neuroblastoma cell line (SH-SY5Y) were used to assess the effects of CGA on AD in vivo and in vitro, respectively. Cognitive function in mice was measured using a Morris water maze (MWM) test. Hematoxylin and eosin, monodansylcadaverine fluorescence, LysoTracker Red (LTR), and immunofluorescence staining were used to evaluate the morphological changes in vivo and in vitro. The protein expressions of autophagy markers (LC3B-II/LC3B-I, p62/SQSTM, beclin1 and Atg5) and lysosomal-function-related markers (cathepsin D, mTOR, p-mTOR P70S6K, p-p70s6k and TFEB) were analyzed with Western blot analyses. Results: CGA treatment significantly improved spatial memory, relieved neuron damage, and inhibited autophagy in APP/PS1 mice (P<0.05). Moreover, CGA notably suppressed autophagosome production and enhanced autophagy flux in SH-SY5Y cells induced by Aβ 25-35 (P<0.05). Further analysis showed that CGA markedly promoted lysosomal activity, and this was accompanied by upregulated cathepsin D protein expression, which was induced by the mTOR/TFEB signaling pathway in APP/PS1 mice and Aβ 25-35 -exposed SH-SY5Y cells (P<0.05). Conclusion: CGA treatment restored autophagic flux in the brain and alleviated cognitive impairments in APP/PS1 mice via enhanced activation of the mTOR/TFEB signaling pathway.

Neuroprotective Effects of Coffee Bioactive Compounds: A Review

“…Several studies focused on the protective effects of chlorogenic acid against the neurotoxicity caused by exposure to Aβ peptide. For example, it displayed significant protective effects towards Aβ 25–35 -induced neuronal damage in PC12 cells as well as in neuroblastoma SH-SY5Y cells [ 298 , 299 ]. In addition, chlorogenic acid suppressed the Aβ 1–42 self-induced aggregation in PC12 cells [ 300 ].…”

“…Importantly, chlorogenic acid significantly inhibited Aβ 25–35 -induced autophagy in SH-SY5Y cells by modulating lysosomal function. In the same study, it elevated protein levels of p-mTOR, p-p70s6k and nuclear transcription factor EB (TFEB) indicating that it may enhance the autophagic flux in Aβ2 5-35 -treated SH-SY5Y cells via the regulation of the mTOR/TFEB signaling pathway [ 299 ].…”

“…Recently, chlorogenic acid has been reported to produce beneficial effects in the APP/PS2 transgenic mice [ 299 ]. These double transgenic mice overexpress mutant forms of human APP and human PS2.…”

Transcription factor EB agonists from natural products for treating human diseases with impaired autophagy-lysosome pathway

“…Reduce APP, CTF-β/α, Aβ and Tau aggregates, improve motor and cognitive function 2. Enhance autophagy, reduce neuronal death, rescue behavioral abnormality [ 55 , 56 ] Curcumin analog E4 ( 3 ) PD Inhibit Akt-mTORC1 N2a cells, HeLa cells, PC12 cells Promote autophagic flux and lysosomal biogenesis, reduce α-synuclein, protect against MPTP toxicity [ 57 ] Resveratrol ( 4 ) Atherosclerosis HUVECs Promote autophagic flux, attenuate endothelial oxidative injury [ 49 ] Oleuropein aglycone ( 5 ) Cardiovascular disease Cardiomyocytes Promote autophagic flux, restore autophagy impairment, protect from cardiotoxicity [ 48 ] Chlorogenic acid ( 6 ) AD Inhibit mTOR Aβ25-35-induced SH-SY5Y cells APP/PS1 mice Ameliorate cognitive deficits, neuronal injury, and Aβ plaque deposition, inhibit The production of autophagosomes, improve autophagic flux, enhance lysosomal activity [ 58 ] Genistein ( 7 ) MPS HDFa cells, HeLa cells, MEFs Inhibit GAG synthesis, enhance lysosomal hydrolases [ 59 ] Genistein ( 7 ) and kaempferol ( 8 ) MPS Inhibit mTOR HDFa and MPS II cells Stimulate the expression of genes coding for GAG degrading enzymes [ 60 ] Quercetin ( 9 ) Neuronal tissues Inhibit mTORC1 ...…”

“…Chlorogenic acid can inhibit the production of autophagosomes, improve the fusion of autophagosomes with lysosomes, and enhance lysosomal function in vitro and in vivo. Moreover, chlorogenic acid effectively ameliorates cognitive deficits, neuronal injury, and Aβ plaque deposition in APP/PS1 mice [ 58 ].…”