(−)-Epigallocatechin-3-Gallate Diminishes Intra-and Extracellular Amyloid-Induced Cytotoxic Effects on Cholinergic-like Neurons from Familial Alzheimer’s Disease PSEN1 E280A

Abstract

Alzheimer’s disease (AD) is a complex neurodegenerative disease characterized by functional disruption, death of cholinergic neurons (ChNs) because of intracellular and extracellular Aβ aggregates, and hyperphosphorylation of protein TAU (p-TAU). To date, there are no efficient therapies against AD. Therefore, new therapies for its treatment are in need. The goal of this investigation was to evaluate the effect of the polyphenol epigallocatechin-3-gallate (EGCG) on cholinergic-like neurons (ChLNs) bearing the mutation E280A in PRESENILIN 1 (PSEN1 E280A). To this aim, wild-type (WT) and PSEN1 E280A ChLNs were exposed to EGCG (5–50 μM) for 4 days. Untreated or treated neurons were assessed for biochemical and functional analysis. We found that EGCG (50 μM) significantly inhibited the aggregation of (i)sAPPβf, blocked p-TAU, increased ∆Ψm, decreased oxidation of DJ-1 at residue Cys106-SH, and inhibited the activation of transcription factor c-JUN and P53, PUMA, and CASPASE-3 in mutant ChLNs compared to WT. Although EGCG did not reduce (e)Aβ42, the polyphenol reversed Ca2+ influx dysregulation as a response to acetylcholine (ACh) stimuli in PSEN1 E280A ChLNs, inhibited the activation of transcription factor NF-κB, and reduced the secretion of pro-inflammatory IL-6 in wild-type astrocyte-like cells (ALCs) when exposed to mutant ChLNs culture supernatant. Taken together, our findings suggest that the EGCG might be a promising therapeutic approach for the treatment of FAD.

(−)-Epigallocatechin-3-gallate, a Polyphenol from Green Tea, Regulates the Liquid–Liquid Phase Separation of Alzheimer’s-Related Protein Tau

“…EGCG has received significant attention because of its protective role in health and disease . In particular, EGCG impedes aggregation of tau, − disassembles preformed tau filaments, , reduces tau hyperphosphorylation or glycation, − and suppresses tau expression . Our study, by systematically investigating the regulatory effect of EGCG on tau LLPS, provides novel insights into the biological activity of EGCG.…”

Cholinergic-like neurons and cerebral spheroids bearing the PSEN1 p.Ile416Thr variant mirror Alzheimer's disease neuropathology

“…It is known that ROS/ H 2 O 2 activate c-JUN, P53, pro-apoptotic PUMA, and CASPASE-3 48 . Unsurprisingly, immunocytochemistry analysis showed that WT ChLNs display neither activated c-JUN (Fig.…”

Trends and hotspots in tea and Alzheimer's disease research from 2014 to 2023: A bibliometric and visual analysis

“…Additionally, EGCG significantly inhibits the aggregation of the protein sAPPβ and reverses Ca 2+ -induced neuroinflammatory responses. It also modulates Ca 2+ endocytosis, inhibits the activation of the transcription factor NF-kappa B, and reduces the secretion of pro-inflammatory IL-6 in astrocyte-like cells, thus inhibiting inflammation and exerting neuroprotective effects [ 45 ]. However, despite numerous studies investigating the specific mechanisms of EGCG's neuroprotective effects on AD molecular, its pharmacological mechanisms remain largely unexplored, and strategies for its use in AD treatment require further exploration [ 46 ].…”