Table 1.

In vitro studies on polyphenols: mechanisms of action in Alzheimer’s disease prevention.

Polyphenol	Chemical Formula	Plant Origin	Experimental Model	Health Effects	Reference
Flavonoids
Apigenin	C15H10O5	Some of the primary sources of apigenin include:   Parsley (Petroselinum crispum) Celery (Apium graveolens) Chamomile (Matricaria chamomilla) Thyme (Thymus vulgaris) Peppermint (Mentha piperita) Oregano (Origanum vulgare) Onions (Allium cepa) Oranges (Citrus sinensis) Artichokes (Cynara scolymus)	Human-induced pluripotent stem cell (iPSC)-derived neurons.   For the inflammation-based assays, neurons were treated with 50 μM apigenin or a vehicle control for 24 h. Following this treatment, the media was replaced with conditioned media from activated microglia for 48 h. In addition to the inflammation assays, the neurons were subjected to oxidative stress by treatment with 300 μM H2O2 or 10 μM SNAP for 24 h, after a 24 h pre-treatment with 50 μM apigenin.	Apigenin: Significant anti-inflammatory and neuroprotective effects. Protects neurons from neurite retraction induced by inflammatory stress. Reduces the release of NO and various pro-inflammatory cytokines. Protects neurons from apoptosis by reducing caspase-3/7 activity. Reduces neuronal hyper-excitability and disturbances in calcium signaling. Decreases both oxidative and nitrosative stress levels.	[184]
Cyanidin-3-O-glucoside Malvidin-3-O-glucoside Pelargonidin-3-O-glucoside Peonidin	Cyanidin-3-O-glucoside: C21H21O11 Malvidin-3-O-glucoside: C23H25O12 Pelargonidin-3-O-glucoside: C21H21O10 Peonidin chloride (Peonidin): C16H13ClO6		SK-N-SH cell line (human neuroblastoma cell line).   The polyphenol formulation tested was MAF14001, an equimolar mixture of cyanidin-3-O-glucoside chloride, malvidin-3-O-glucoside chloride, pelargonidin-3-O-glucoside chloride, and peonidin chloride. This formulation was tested at concentrations ranging from 5 to 20 µM. The administration mode involved direct addition of MAF14001 to the cell culture medium. The cells were incubated with the formulation for 24 h to assess the protective effects against Aβ peptide-induced toxicity.	MAF14001, a mixture of anthocyanins and anthocyanidins: Protects SK-N-SH cells against Aβ-induced toxicity. Prevents Aβ-induced oxidative stress, mitochondrial dysfunction, and apoptosis Interacts with Aβ to prevent its aggregation, a key process in Aβ-induced oxidative stress. Decreases TAU phosphorylation induced by Aβ.	[185]
Epicatechin (EC) Catechin (CE)		Theobroma cacao	Mouse hippocampal cell lines HT-22. Primary neuronal cultures.   The cells were treated with Aβ oligomers (12.5 µM) for 24 h to mimic AD.   Differentiated cells were treated with cocoa extract containing 30 µg/mL EC, 10 µg/mL CE, and 170 µg/mL total polyphenols for 4 days.	Cocoa polyphenolic extract: Exerts neuroprotective effects by activating the BDNF survival pathway. This activation counteracted neurite dystrophy induced by Aβ plaques and oligomers, suggesting the potential of cocoa polyphenols as preventive agents against neurodegenerative diseases, such as AD by reducing oxidative stress and promoting neuronal survival.	[186]
Epicatechin (EC) Catechin (CE) Procyanidins	EC: C15H14O6 CE: C15H14O6 Procyanidins: Varies depending on the degree of polymerization (DP)	Theobroma cacao	Mouse brain hippocampal slices.   Slices were exposed to 25 µM and 100 µM concentrations of cocoa extracts. The hippocampal slices were initially acclimated in oxygenated artificial cerebrospinal fluid and subsequently incubated with the cocoa extracts at 32 °C for a duration of 1 h.	Cocoa polyphenolic extract: Reduces Aβ oligomer formation. Prevents synaptic deficits induced by Aβ oligomers. Restores long-term potentiation reduced by oligomeric Aβ.
Epigallocatechin-3-gallate (EGCG)	C22H18O11	Camellia sinensis	Human SH-SY5Y neuroblastoma cells and Chinese hamster ovary.   Cells transfected with human APP695 were treated with 1–10 μM EGCG for 2 days.	EGCG: Demonstrates potent iron-chelating activity comparable to that of desferrioxamine. Significantly reduces both APP and toxic Aβ peptide production Promotes non-amyloidogenic APP processing through increased secretion of soluble APP-α and activation of PKC.	[187]
Epigallocatechin-3-gallate (EGCG)	C22H18O11	Camellia sinensis	Cholinergic-like neurons (ChLNs) derived from umbilical cord mesenchymal stem cells with either wild-type or PSEN1 E280A mutation.   The cells were exposed to varying concentrations of EGCG, ranging from 5 to 50 µM, with 50 µM selected for further experiments based on its efficacy in previous tests. The EGCG was administered directly into the regular culture medium for a duration of 4 days post-transdifferentiation.	EGCG: Inhibits APP aggregation. Blocks the phosphorylation of TAU (p-TAU), increases mitochondrial membrane potential (∆Ψm), and decreases oxidation of DJ-1 at the residual Cys106-SH. Inhibits the activation of transcription factors c-JUN and P53, as well as PUMA and CASPASE-3, in mutant ChLNs compared to WT. Reverses Ca2+ influx dysregulation in response to ACh stimuli in PSEN1 E280A ChLNs. Inhibits the activation of the transcription factor NF-κB and reduces the secretion of the pro-inflammatory cytokine IL-6 in wild-type astrocyte-like cells when exposed to the culture supernatant from mutant ChLNs.	[188]
Luteolin (LUT)	C15H10O6	Various plants including parsley, thyme, and celery	Human neuroblastoma BE(2)-M17 cells   Cells were pre-treated DHA, LUT, and urolithin A (UA), each at a concentration of 5 µM in combination (D5L5U5) and individually at 30 µM, 20 µM, and 30 µM respectively. The pre-treatment lasted for 24 h, after which the cells were exposed to 20 µM of oligomeric Aβ1–42 for various durations ranging from 4 to 72 h	DHA, LUT, and UA in combination (D5L5U5): Have potent inhibitory effects against Aβ1–42-induced toxicity through protecting mitochondria. These effects include minimizing oxidative stress, increasing ATP levels, and inducing mitophagy and mitobiogenesis.	[189]
Quercetin Thymol	Quercetin: C15H10O7 Thymol: C10H14O	Quercetin: found in Allium cepa, asparagus, red leaf lettuce, apple, and berries. Thymol: major component of Thymus vulgaris.	PC12 cell model   The concentrations of the polyphenols used were 40 µM for quercetin and 35 µg/mL for thymol, while the concentrations of Allium cepa extract were 1000 µg/mL and Thymus vulgaris essential oil was 0.4 ppm. The incubation period for these treatments was 48 h. The cell model was created using formaldehyde at a final concentration of 0.35 mM to induce AD-like conditions in the PC12 cells.	Quercetin: Reduces the rate of apoptosis in AD cells significantly better than other compounds. Increases the expression of genes related to AD, such as PP2A, GSK3, and NMDAR. Thymol: Shows anti-AD and antioxidant effects, increases cell survival rate, and reduces apoptosis rate. Both thymol and Thymus vulgaris essential oil significantly increase the expression of the PP2A gene.	[190]
Phlorotannins
Eckol, 6,6′-Bieckol, 8,8′-Bieckol Dieckol Phlorofucofuroeckol-A (PFF-A)	Eckol: C18H12O9 6,6′-Bieckol and 8,8′-Bieckol: C36H22O20 Dieckol: C36H22O18 Phlorofucofuroeckol-A: C30H18O13	Ecklonia cava	SK-N-SH neuroblastoma cells.   Cells were exposed to 2 μL of 50 mM of each polyphenol for 24 h.	Ecklonia cava extract: Inhibits AChE activity (IC50 from 16.0 to 96.3 μM). Shows a potent BuChE inhibitory activity, particularly phlorofucofuroeckol-A (PFF-A) with an IC50 of 0.95 μM. Inhibits GSK-3β, which is involved in the formation of hyper p-TAU and generation of Aβ. Bieckol and PFF-A inhibit APP biosynthesis. PFF-A exhibits strong β-BACE-1 inhibitory activity.	[191]
Phenylpropanoids, Flavonoids, and Hydroxycinnamic acids
Phenylpropanoids Flavonoids Hydroxycinnamic acids		Arabidopsis thaliana mutants, including prn1, cop1, and xpf3	Primary mixed glial cultures derived from the cerebral cortex of neonatal APOE-targeted-replacement (APOE-TR) and APOE-knock-out (KO) mice.   These cultures contained approximately 95% astrocytes and 5% microglia.   Cells were treated with the plant extracts at a concentration of 150 µg/mL, either with or without inflammatory stimuli (LPS or Aβ oligomers). Incubation times included pre-treatment periods followed by inflammatory stimulation, with TNFα levels measured after 16 h.	Polyphenol-enriched extracts from Arabidopsis thaliana mutants: Exhibits anti-inflammatory effects, especially the xpf3 mutant. Attenuates TNF-α secretion in mixed glial cultures, with a notable reduction observed in APOE4 cultures compared to APOE3 and APOE2. Could serve as a potential therapeutic agent for AP-OE-modulated neuroinflammation, a characteristic of AD.	[192]
Stilbenes
Resveratrol	C14H12O3	Grapes and red wine	HEK293 cells stably transfected with human APP695. N2a cells stably transfected with wild-type or Swedish mutant human APP695 cDNAs.   Cells were treated with 20–40 µM resveratrol for 24 h or 10 or 20 µM resveratrol for 12, 48, and 72 h.	Resveratrol: Decreases levels of secreted and intracellular Aβ peptides in the cell lines. Does not inhibit Aβ production but promotes intracellular degradation of Aβ via a mechanism involving proteasome involvement. Decreases in Aβ could be prevented by selective proteasome inhibitors and by siRNA-directed silencing of the proteasome subunit β5. Demonstrates a proteasome-dependent anti-amyloidogenic activity, suggesting therapeutic potential in AD.	[193]
Resveratrol	C14H12O3	Resveratrol is derived from grapes	Rat glioma cell line C6. These cells are classified as part of the astrocyte lineage.   The cells were treated with LPS at a concentration of 1 μg/mL. The treatments included exposure to LPS alone for 6 and 24 h, and combinations of LPS with resveratrol (25 μM) for 24 h.	Resveratrol: Decreases TAU hyperphosphorylation induced by LPS. Increases APP expression. Has a potential therapeutic role in reducing neuroinflammation and modifying the expression of proteins associated with AD.	[194]
Trans ε-viniferin Resveratrol.	Trans ε-viniferin—C28H22O6 Resveratrol—C14H12O3	Vine shoots (Vitis vinifera)	Murine primary co-cultures of neurons and astrocytes were prepared from the hippocampus and cortex of embryonic day 18 (E18) mice.   The cultures were first pre-treated with either 1 μM of trans ε-viniferin or resveratrol, or with 0.001% DMSO as a vehicle control, in a medium with serum for 24 h. Following this pre-treatment, the cultures were then treated for 48 h in a serum-free medium with 20 μM Aβ42, which had been previously aggregated by incubation for 72 h at 37 °C, and 200 pg/mL IL-1β to mimic the inflammatory context of AD. The selection of the 1 μM concentration for the polyphenols was based on preliminary cytotoxicity assays that showed higher concentrations of trans ε-viniferin were cytotoxic, whereas 1 μM was not.	Trans ε-viniferin: Induces the disaggregation of Aβ peptide and rescues inflammation.   These effects were higher than those of resveratrol, making trans ε-viniferin a promising multi-target therapeutic candidate for AD.	[195]
Tannins
Tannic acid (TA) Epigallocatechin gallate (EGCG)	TA: C76H52O46 EGCG: C22H18O11	TA: Found in various plant species, including oak, sumac, and witch hazel. Epigallocatechin gallate (EGCG): Major component of green tea leaves (Camellia sinensis)	SH-SY5Y neuronal cells   Cells were treated with 20 μM concentrations of TA and EGCG	TA: Acts as a dual-acting therapeutic agent against AD and ferroptosis. Modulates Aβ42 and TAU aggregation. Chelates metal ions, reducing oxidative stress. Rescues mitochondrial function. Activates and enhances GPX4 levels, inhibiting ferroptosis. Activates Nrf2, regulating ferroptosis in neuronal cells. Inhibits lipid peroxidation and protein oxidation, providing neuroprotective effects.   EGCG: Inhibits Aβ42 aggregation. Shows antioxidant properties, reducing oxidative stress. Does not directly activate GPX4 but inhibits RSL3-induced GPX4 inhibition.	[196]

AD: Alzheimer’s disease; Aβ: Amyloid-beta; BDNF: brain-derived neurotrophic factor; EC: epicatechin; CE: catechin; DHA: docosahexaenoic acid; EGCG: epigallocatechin-3-Gallate; APP: amyloid precursor protein; p-TAU: phosphorylated tau; ∆Ψm: mitochondrial membrane potential; DMSO: dimethyl sulfoxide; IL-1β: interleukin-1 beta; TA: tannic acid; GPX4: glutathione peroxidase 4; Nrf2: nuclear factor erythroid 2-related factor 2; LPS: lipopolysaccharide; PKC: protein kinase C; PUMA: p53-upregulated modulator of apoptosis; CASPASE-3: cysteine–aspartic proteases-3; WT: wild-type; PSEN1: presenilin 1; APOE: apolipoprotein E; TR: targeted replacement; KO: knock-out; SK-N-SH: human neuroblastoma cell line; HT-22: mouse hippocampal cell line; BE(2)-M17: human neuroblastoma cell line; PC12: rat pheochromocytoma cell line; SH-SY5Y: human neuroblastoma cell line; iPSC: induced pluripotent stem cell; NO: nitric oxide; SNAP: S-nitroso-N-acetylpenicillamine; TNFα: tumor necrosis factor alpha; DJ-1: protein deglycase DJ-1; NMDAR: N-methyl-D-aspartate receptor; PP2A: protein phosphatase 2A; GSK3: glycogen synthase kinase 3; MAF14001: anthocyanin/anthocyanidin formulation.