Potential of Caffeine in Alzheimer’s Disease—A Review of Experimental Studies
Abstract
:1. Introduction
2. Caffeine—Main Mechanisms of Action
3. Alzheimer’s Disease (AD)
4. Caffeine in Alzheimer’s Disease
5. Experimental Models of AD
5.1. Effects of Caffeine in Experimental Animal Models of AD
5.1.1. Transgenic Rodent Models
5.1.2. Non-Transgenic Rodent Models
5.1.3. Rabbit Cholesterol-Induced Model
5.1.4. Nematode Models
5.2. In Vitro Studies
5.3. In Silico Studies
6. Discussion
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Model | Caffeine Dose and Study Conditions | Aim | Effects | Reference |
---|---|---|---|---|
APPswe (K670N/ M671L) male and female mice | Caffeine: 0.3 g/L p.o. in drinking water for 5.5 months; start: 4-month-old mice, 8-month-old at the start of behavioral tests, 9.5-month-old at the end of behavioral tests | To investigate the possible neuroprotective effects of long-term dietary caffeine intake in APPswe transgenic mice. | Caffeine protected against cognitive impairment. It reduced Aβ levels in the hippocampus, restored brain adenosine levels, but did not affect the A1R and A2AR hippocampal density and expression in the cerebral cortex and hippocampus. | [129] |
APPswe (K670N/ M671L) mice | Caffeine: 1.5 mg p.o. for 2 weeks, every 12 h; start: 9.5-month-old mice | To investigate the effects of caffeine on the signal transduction pathways (PKA, CREB, JNK and ERK) in cognitively important areas of the brain. | Caffeine showed beneficial effects in the brain function and exerted neuroprotective and antiapoptotic effect by stimulating PKA activity, increasing the level of phosphorylated CREB and decreasing JNK and ERK phosphorylation. | [128] |
APPswe (K670N/ M671L) mice | Caffeine: 0.6 mg/day in drinking water for 1 month; start: 11- to 12-month-old mice | To explain the protective mechanism of caffeine and melatonin administration against cognitive dysfunction in transgenic APPswe mice. | Caffeine and melatonin prevented cognitive impairment. Caffeine slightly increased mitochondrial functions, however it inhibited the enhancement of mitochondrial functions provided by melatonin. | [133] |
APPswe (K670N/ M671L) and Indiana (V717F) mutation male mice | 0.0395% crude caffeine (95.95% caffeine, 1.1% moisture, 1.04% fat, 0.1% ash) in diet or 0.0375% pure caffeine in diet for 2 months; start: 3-month-old mice | To investigate the effects of consumption of crude and pure caffeine on the learning and memory processes in transgenic AD mice. | Crude and pure caffeine administered for two months partly prevented memory deficits (crude caffeine exerted greater effect). Crude caffeine (but not pure) reduced Aβ1-42 levels, suppressed Aβ accumulation and reduced the number of Aβ plaques in the hippocampus. Both prevented Aβ-induced neuronal cell death and exerted antiapoptotic activity suppressing caspase-3 activity. Antioxidant and anti-inflammatory effects of crude caffeine were also demonstrated in APPswe mice. | [131] |
APPswe mice and APPswe/PS1 mice | Caffeine: 1.5 mg i.p., single administration, 3- to 4-month-old APPswe mice; caffeine: 1.5 mg i.p. or p.o., single administration, 14-month-old APPswe mice; caffeine: 1.5 mg i.p., single administration, 14-month-old APPswe/PS1 mice; caffeine: 1.5 mg p.o. twice-daily for 7 days, 15- to 20-month-old APPswe/PS1 mice; caffeine: 1.5 mg p.o., two administrations on one day every 4th day for 2 months, 20-month-old APPswe/PS1 mice; | To investigate the effects of acute and long-term caffeine administration on the cognitive performance and Aβ levels in APPswe and APPswe/PS1 transgenic mice. | Long-term caffeine intake improved cognitive functions in APPswe and APPswe/PS1 mice. Decreased Aβ levels in the plasma were observed after single administration of caffeine and long-term caffeine treatments in both transgenic mice models. Chronic caffeine treatment reduced soluble Aβ level in the cortex and hippocampus and insoluble Aβ level in the hippocampus in APPswe mice. Acute caffeine administration rapidly reduced the Aβ level also in the interstitial fluid in the hippocampus but did not affect Aβ elimination in APPswe mice. | [134] |
APPswe/PS1 mice and APPswe mice, control non-transgenic mice | Caffeine: 0.3 mg (unconcentrated coffee) i.p., single administration or 1.5 mg (concentrated coffee) i.p., single administration or 0.06 mg (concentrated decaffeinated coffee) i.p., single administration, 6- to 8-month-old APPswe/PS1 transgenic mice; caffeine: 0.75 mg (concentrated coffee) p.o., twice weekly for 3 months or 0.03 mg (decaffeinated coffee) p.o., twice weekly for 3 months, 10-month-old APPswe transgenic mice | To investigate the effects of acute and long-term treatment with coffee or decaffeinated coffee (to compare the effect of caffeine to coffee) on the plasma cytokine and Aβ levels and behavior (only after long-term treatment) in transgenic mice models of AD. | Acute caffeine intake increased the level of G-CSF and IL-10 in plasma (concentrated and unconcentrated coffee) and IL-6 level in plasma (only concentrated coffee). Higher plasma caffeine concentrations were related to lower levels of Aβ in plasma. Single treatment with coffee (concentrated and unconcentrated) increased G-CSF, IL-6 and IL-10 plasma levels also in non-transgenic mice. Long-term treatment with concentrated coffee (but not decaffeinated coffee) favorably affected cognitive interference task and elevated level of G-CSF (but not other cytokines) in plasma in transgenic mice. Improvement of cognitive performance was associated with higher G-CSF levels suggesting that elevated G-CSF levels may be associated with possible beneficial effects of coffee against AD. | [136] |
APPswe/PS1 mice | Caffeine: 0.75 mg/day or 1.5 mg/day p.o. for 8 weeks; 12-month-old mice | To investigate the effects of caffeine intake on the memory deficits, BDNF and TrkB expression in APPswe/PS1 double transgenic mice. | Caffeine at both doses used increased spatial learning ability and memory capability. Caffeine treatment increased the expression of hippocampal BDNF and TrkB. Caffeine exerted protective role against memory impairment in APPswe/PS1 mice. | [132] |
THY-Tau22 male mice | Caffeine: 0.3 g/L p.o. in drinking water for 10 months; start: 2-month-old mice | To investigate the effects of chronic caffeine intake on the development of hippocampal tau protein pathologies and spatial memory disorders in THY-Tau22 transgenic mice. | Chronic caffeine intake prevented spatial memory deficits and improved memory performance. Caffeine effect was associated with a reduction of neuroinflammation and decrease in the hippocampal level of hyperphosphorylated tau protein. Caffeine treatment decreased oxidative stress (reduced expression of MnSOD and EAAT3) in THY-Tau22 mice. | [104] |
THY-Tau22 female mice | Caffeine: 0.3 g/L p.o. in drinking water; start of caffeine administration: 2 weeks before mating; end of caffeine administration: 15th postnatal day; 8- or 12-month-old at the start of behavioral tests. | To investigate the effects of long-term caffeine exposure during pregnancy in offspring in THY-Tau22 transgenic mice. | The exposure to caffeine during pregnancy induced physiological disorders and accelerated cognitive disorders in THY-Tau22 transgenic mice model and may be a risk factor for early stages of AD. | [105] |
3xTg (APPswe, PS1/M146V and tau P301L) male mice, control non-transgenic mice | Caffeine: 0.3 mg/mL in drinking water p.o. for 7 months; start: 6-month-old mice; behavioral testing at 13 months of age. | To investigate the effects of long-term caffeine administration on the memory and learning in 3xTg-AD mice with behavioral and psychological symptoms of dementia (BPSD) profile. | Caffeine increased motor activity, total horizontal activity and emotionality in the behavioral tests in non-transgenic mice and reduced it in 3xTg-AD mice. Caffeine administration increased spontaneous motor activity (to a greater extent at night) only in 3xTg-AD mice. Results indicate that aggravation of BPSD-like behaviors, anxiety-related behaviors or neophobia adversely affected possible beneficial effects of caffeine treatment (improvement of memory and learning) in 3xTg-AD mice. | [135] |
Model | Caffeine Dose and Study Conditions | Aim | Effects | Reference |
---|---|---|---|---|
Adult CF1 male mice administered with Aβ25–35 i.c.v. (3 nmol; volume: 3 μL) | Caffeine: 1 mg/mL p.o. in drinking water (22 mg/kg/day) for 12 days, Aβ i.c.v. on 7th day; caffeine: 30 or 80 mg/kg i.p., single administration, 30 min before Aβ i.c.v. caffeine: 30 mg/kg for 4 days, Aβ i.c.v. after 2 days of caffeine intake; caffeine: 1 mg/mL p.o. in drinking water (for 12 days) and 30 mg/kg i.p., single administration, 30 min before Aβ i.c.v.; behavioral tests were performed 8–9 days after Aβ i.c.v. administration. | To investigate the effects of caffeine and a selective A2AR antagonist against cognitive impairment in AD induced by i.c.v. Aβ25–35 administration in mice. | Blockade of A2AR by caffeine or by a selective A2AR antagonist prevented cognitive impairment, neurodegeneration and brain destruction in Aβ-induced AD mice model. | [117] |
Adult male Sprague-Dawley rats with accelerated aging induced by d-galactose administration (120 mg/kg i.p. for 60 days) | Caffeine: 3 mg/kg/day i.p. for 60 days (during d-galactose treatment period) | To investigate the effects of chronic caffeine intake on neurodegeneration induced by d-galactose-aging rat model. | Chronic caffeine intake reduced oxidative stress (decreased 8-oxoguanine level), neuroinflammation, neuronal cells apoptosis, neurodegeneration, synaptic dysfunction and memory deficits induced by d-galactose injections. | [119] |
Adult male Wistar rats with AD induced by i.c.v. administration of STZ (3 mg/kg; single bilateral administration) | Caffeine: 1 g/L in drinking water for 2 weeks before and 4 weeks after STZ administration. Behavioral tests 4 weeks after STZ administration | To investigate the effects of caffeine intake on the expression and density of adenosine receptors and hippocampal neurodegeneration in STZ-induced rat model of AD. | Caffeine administration prevented the STZ-induced memory deficits, sporadic dementia, neurodegeneration and decreased expression and density of A2AR in the hippocampus. | [141] |
Adult male Sprague-Dawley rats treated with AlCl3 (17 mg/kg p.o. for 4 weeks) | Caffeine 1.5 mg/kg p.o. for 4 weeks concurrently with AlCl3 or two weeks before the start and for 4 weeks during AlCl3 administration | To investigate the effects of caffeine on the histological picture of hippocampus, expression of BDNF, TrkB, and immunoreactivity of Ki-67 and GFAP in the hippocampus in rats with AlCl3-induced AD. | Caffeine intake exerted neuroprotective activity (improvement of histological hippocampus picture, stronger Ki-67 and weaker GFAP immunoreactivity, increased BDNF and TrkB gene expression). The effects were stronger in rats treated with caffeine also before the start of AlCl3 administration. | [142] |
Adult male Wistar rats treated with AlCl3 (100 mg/kg p.o. for 30 days) | Caffeine: 20 mg/kg i.p. for 30 days, 1 h before AlCl3 p.o. intake | To evaluate an antioxidant, anti-inflammatory and anticholinesterase properties of caffeine against AlCl3-induced neurotoxicity in rats. | Caffeine exerted neuroprotective, antioxidant and anticholinesterase activity against AlCl3-induced neurotoxicity in rats. It reduced oxidative stress parameters (NO level), decreased AChE and Na+/K+-ATPase activity in the cerebral cortex and hippocampus (Na+/K+-ATPase activity also in the striatum). Caffeine revealed also anti-inflammatory properties by reducing the increased TNF-α levels in the hippocampus and striatum associated with AlCl3-induced neurotoxicity. | [143] |
Fisher-344 young male rats (3-month-old) treated with LPS (0.250 µg/h i.c.v. by osmotic minipump for 4 weeks); Fisher-344 male aged rats (24-month-old) | Caffeine: 0.5, 5, 10, 20 or 40 mg/kg/day i.p. for 2 or 4 weeks to young rats; caffeine: 40 mg/kg/day i.p. for 2 weeks to aged rats | To investigate the effects of different caffeine doses in LPS-induced neuroinflammation in young rats and in age-related neuroinflammation in aged rats (with naturally increased level of microglia activation). | Caffeine exerted potential protective effect against LPS-induced neuroinflammation. It was demonstrated that caffeine may decrease neuroinflammation by a reduction in the number of activated microglial cells in the hippocampus and through regulation of glutamate neurotransmission. | [122] |
C57BL/6N male mice treated with LPS (250 µg/kg i.p. for 2 weeks; 7 doses in 2 weeks) | Caffeine: 30 mg/kg/day i.p. for 6 weeks | To investigate the effect of caffeine administration against LPS-induced oxidative stress, neuroinflammation, apoptotic cell death, neurodegeneration and synaptic impairment in mice. | Caffeine reduced LPS-induced oxidative stress, neuroinflammation and synaptic dysfunctions (increased expression of Nrf2, HO-1 and Bcl-2, reduced expression of TLR-4, p-NF-κB, p-JNK, BAX, caspase-3, TNF-α, COX-2, NOS-2 and synaptic markers) in mouse brains. | [123] |
CF1 male mice (3-4-month-old) with cholinergic blockade induced by a single scopolamine hydrobromide administration (2 mg/kg i.p.) | Caffeine: 10 mg/kg i.p. for 4 days before scopolamine hydrobromide administration; scopolamine administration: 15 min before or immediately after the inhibitory avoidance test, immediately after training session in the novel object recognition task, 90 min before the open field test; independent group of mice for each test | To investigate the effect of caffeine intake on short-term and long-term memory impairment induced by a single scopolamine administration, assessed in three behavioral tests. | Pretreatment with caffeine prevented scopolamine-induced impairment in the acquisition phase when short-term memory was assessed in the inhibitory avoidance task, and in the consolidation phase when short-term and long-term memory were assessed in the inhibitory avoidance task. Caffeine administration prevented scopolamine-induced short-term and long-term memory deficits (assessed in the novel object recognition task). Caffeine exerted beneficial effect in the cholinergic-induced memory disruption. There was no effect of caffeine treatment on the spontaneous locomotor activity assessed in the open field test. | [115] |
Model | Caffeine Dose and Study Conditions | Aim | Effects | Reference |
---|---|---|---|---|
New Zealand white rabbits (1.5- to 2-years-old) fed a 2% cholesterol-enriched diet | Caffeine: 3 mg/day in 50 mL of drinking water for 12 weeks | To investigate the effects of caffeine on BBB leakage in rabbits fed a cholesterol-enriched diet as a model of sporadic AD. | Chronic caffeine administration prevented dysfunction of BBB, decreased activation of astrocytes and decreased density of microglia induced by high cholesterol diet in rabbits. | [155] |
New Zealand white male rabbits (1.5- to 2-years-old) fed a 2% cholesterol-enriched diet | Caffeine: 0.5 mg/day or 30 mg/day in drinking water for 12 weeks | To investigate the effects of caffeine treatment on molecular mechanisms of AD-like pathology in the cholesterol-fed rabbit model of AD. | Chronic caffeine intake decreased Aβ accumulation in the hippocampus and reduced hyperphosphorylated tau protein level in the hippocampus (reduced phosphorylated GSK-3β enzyme level). Caffeine prevented oxidative damage (reduced ROS generation and H2O2 production, increased GSH/GSSG ratio) and restored the level of A1R, reduced by cholesterol in rabbits. Caffeine did not affect the level of A2AR and RyRs and the cholesterol concentration in plasma. | [156] |
Model | Caffeine Dose and Study Conditions | Aim | Effects | Reference |
---|---|---|---|---|
Caenorhabditis elegans strains: wild-type N2, CL2006 dvIs2 | Ilex paraguariensis hydroalcoholic extract (IPHE): 2 or 4 mg/mL (41 or 87 μM caffeine); caffeine: 200 or 400 μM. Treatment since first larval stage till required age for test. | To investigate the effects of IPHE and caffeine administration on the Aβ-induced toxicity in Caenorhabditis elegans. | IPHE and caffeine extended lifespan of worms, decreased AChE activity and reduced Aβ deposition and toxicity leading to worms’ paralysis. IPHE and caffeine reduced also Aβ mRNA levels and increased expression of hsp-16.2 (chaperone protein which overexpression causes suppression of Aβ-toxicity). After both treatments an antioxidant activity (reduced ROS levels) was observed. | [161] |
Various Caenorhabditis elegans strains | 10% coffee extract (3.6 mM caffeine); | To investigate the effects of coffee extract treatment on the Aβ-induced toxicity in Caenorhabditis elegans. | Coffee extract prevented Aβ-induced toxicity in the transgenic models of AD in Caenorhabditis elegans. It induced also a delay in the paralysis progression in worms. No reduction in Aβ expression, Aβ aggregation and distribution was observed in coffee-treated group. The beneficial effect of coffee may result from skn-1/Nrf2 pathway induction. | [160] |
Caenorhabditis elegans strains: wild-type N2, CL4176 dvls27, TJ356 zIs356, CF1553 muIs84 | 0.1, 0.2 and 0.4 mg/mL Zijuan Pu’er tea water extract (ZTWE) containing: (+)-catechins, caffeine, procyanidins. Mixture of three main constituents in ZTWE: (+)-catechins, caffeine, procyanidins—MCCP. | To investigate the effects of ZTWE and MCPP on the Aβ-induced toxicity in various Caenorhabditis elegans strains. | ZTWE and MCCP delayed Aβ-induced paralysis in worms. MCCP alleviated AD progression and pathologies related to AD due to reduced Aβ-induced toxicity (decreased Aβ aggregation), and increased antioxidant activity (activated DAF-16 signaling pathway associated with oxidative stress resistance; decreased ROS production). | [162] |
Caenorhabditis elegans strains: wild-type N2, CL4176 dvls27, CL2006, AM141, HA759, rtIs11, TJ375, CL2166 | Guarana hydroalcoholic extract (GHE) containing: caffeine: 166.1 μg/mL, theobromine: 2.5 μg/mL, catechin: 34.6 μg/mL, epicatechin: 36.3 μg/mL. 10 or 50 mg/mL GHE | To investigate the effects of GHE treatment in Caenorhabditis elegans models of AD. | GHE prevented Aβ-induced toxicity in the transgenic models of AD in Caenorhabditis elegans. GHE delayed paralysis in nematodes, reduced ROS level and activated protein degradation. DAF-16 and skn-1 are responsible for the beneficial effect against Aβ-induced toxicity. | [158] |
Model | Caffeine Dose and Study Conditions | Aim | Effects | Reference |
---|---|---|---|---|
Primary cortical neurons from 12- to 17-day-old cultures from 3xTg (APPswe, PS1/M146V KI and tau P301L) mouse embryos | Caffeine: 25 mM | To investigate the effects of caffeine treatment on disorders in Ca2+ homeostasis in the primary cortical neurons obtained from 3xTg-AD mice, assessed by microfluorimetric measurements of Ca2+ concentration. | Caffeine treatment increased Ca2+ content in the cortical neurons of 3xTg-AD mice. Caffeine increased release of Ca2+ from RyR-sensitive Ca2+ stores. Enhanced Ca2+ response to the caffeine was probably associated with an increased expression of RyRs in the cortical neurons. | [107] |
Prefrontal cortex brain slices from 3xTg (APPswe, PS1/M146V KI, and tau P130L) mice (1- to 3-month-old) | Caffeine: 10 mM | To investigate the relationship between Ca2+ influx by NMDA receptors and RyR activation in 3xTg-AD mice. | Caffeine stimulated RyRs increasing synaptic excitability. RyR and NMDA receptor activation increased Ca2+ release in 3xTg-AD mice. | [163] |
Human neuroblastoma SH-SY5Y cells treated with 2 μM Aβ25–35 or 10 μM AlCl3 or combined | Caffeine: 10 μM; caffeine: 1-100 μM in the cell viability test | To investigate the role of A1R and A2AR in the neuroprotective activity of caffeine in the AlCl3- and Aβ25–35-induced models of AD in human SH-SY5Y neuroblastoma cells. | Neuroprotective effect of caffeine observed in the combined AlCl3- and Aβ25–35 -induced model of neurotoxicity required a dual antagonism of A1R and A2AR (probably due to combined involvement in the restoration of Ca2+ homeostasis). Caffeine prevented neuronal cell death and exerted antioxidant activity (reduced ROS production, increased SOD activity and decreased MDA concentration). | [164] |
Human neuroblastoma SH-SY5Y cells treated with 20 μM Aβ25–35 | Caffeine: 0.6 or 1 mM | To investigate the mechanism of neuroprotective activity of caffeine against Aβ-induced neurotoxicity in the human neuroblastoma SH-SY5Y cells. | Caffeine prevented Aβ-induced toxicity in neuronal cells, which probably resulted from the blockade of adenosine receptors (A1 and A2A), blockade of NMDA receptors and activation of RyRs. | [165] |
Primary hippocampal neurons from 2- to 5-day-old Sprague-Dawley rats or dorsal root ganglion (DRG) from 1- to 4-day-old Sprague-Dawley rats; both transfected with human APP fused to EGFP or mutant h-tau protein fused to DsRed2 | Caffeine: 50 μM | To investigate the effects of caffeine and various drugs treatment after viral delivery of mutated APP and h-tau protein in the primary hippocampal cells and DRG cells on the degeneration and neuronal cell death. | Experiments demonstrated that delivering mutated APP and h-tau protein accelerated neuronal cell death and morphological damage. Caffeine administration ameliorated APP-induced and tau-induced neuronal damage. Caffeine treatment exerted neuroprotective effects in APP-induced and tau-induced models (prevented morphological damage in both models, increasing the number of healthy neurons). | [166] |
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Londzin, P.; Zamora, M.; Kąkol, B.; Taborek, A.; Folwarczna, J. Potential of Caffeine in Alzheimer’s Disease—A Review of Experimental Studies. Nutrients 2021, 13, 537. https://doi.org/10.3390/nu13020537
Londzin P, Zamora M, Kąkol B, Taborek A, Folwarczna J. Potential of Caffeine in Alzheimer’s Disease—A Review of Experimental Studies. Nutrients. 2021; 13(2):537. https://doi.org/10.3390/nu13020537
Chicago/Turabian StyleLondzin, Piotr, Milena Zamora, Beata Kąkol, Aleksandra Taborek, and Joanna Folwarczna. 2021. "Potential of Caffeine in Alzheimer’s Disease—A Review of Experimental Studies" Nutrients 13, no. 2: 537. https://doi.org/10.3390/nu13020537