Dementia caused by Alzheimer’s disease (AD) is mainly characterized by accumulation in the brain of extra- and intraneuronal amyloid-β (Aβ) and tau proteins, respectively, which selectively affect specific regions, particularly the neocortex and the hippocampus. Sporadic AD is mainly caused by an increase in apolipoprotein E, a component of chylomicrons, which are cholesterol transporters in the brain. Recent studies have shown that high lipid levels, especially cholesterol, are linked to AD. Adenosine is an atypical neurotransmitter that regulates a wide range of physiological functions by activating four P1 receptors (A1, A2A, A2B, and A3) and P2 purinergic receptors that are G protein-coupled. A1 receptors are involved in the inhibition of neurotransmitter release, which could be related to AD. The aim of the present work was to study the effects of a lard-enriched diet (LED) on cognitive and memory processes in adult rats (6 months of age) as well as the effect of theobromine on these processes. The results indicated that the fat-enriched diet resulted in a long-term deterioration in cognitive and memory functions. Increased levels of Aβ protein and IL-1β were also observed in the rats fed with a high-cholesterol diet, which were used to validate the AD animal model. In addition, the results of qPCR and immunohistochemistry indicated a decrease in gene expression and distribution of A1 purinegic receptor, respectively, in the hippocampus of LED-fed rats. Interestingly, theobromine, at both concentrations tested, restored A1 receptor levels and improved cognitive functions and Aβ levels for a dose of 30 mg/L drinking water.
GötzJ, MatamalesM, GötzN, IttnerL, EckertA (2012) Alzheimer’s disease models and functional genomics-How many needles are there in the haystack?Front Physiol3, 1–14.
2.
MizunoS, LijimaR, OgishimaS, KikuchiM, MatsuokaY, GhoshS, MiyamotoT, MiyashitaA, KuwanoR, TanakaH (2012) AlzPathway: A comprehensive map of signalling pathways of Alzheimer's disease. BMC Syst Biol6, 1–10.
3.
ChuL (2012) Alzheimer’s disease: Early diagnosis and treatment. Hong Kong Med J18, 228–237.
4.
PrasanthiJ, DasariB, MarwarhaG, LarsonT, ChenX, GeigerJ, GhribiO (2010) Caffeine protects against oxidative stress and Alzheimer’s disease-like pathology in rabbit hippocampus induced by cholesterol-enriched diet. Free Radic Biol Med49, 1212–1220.
5.
LiuCC, KanekiyoT, XuH, BuG (2013) Apolipoprotein E and Alzheimer disease: Risk, mechanisms, and therapy. Nat Rev Neurol9, 106–118.
6.
HoltzmanDM, HerzJ, BuG (2012) Apolipoprotein E and Apolipoprotein receptors: Normal biology and roles in Alzheimer’s disease. Cold Spring Harb Perspect Med2, 1–23.
7.
RohnTT (2013) Proteolytic cleavage of Apolipoprotein E4 as the keystone for the heightened risk associated with Alzheimer’s disease. Int J Mol Sci14, 14908–14922.
8.
ChenJF, ChernY (2011) Impacts of methylxanthines and adenosine receptors on neurodegeneration: Human and experimental studies. Handb Exp Pharmacol267–310.
9.
StoneTW, CerutiS, AbbracchioMP (2009) Adenosine receptors and neurological disease: Neuroprotection and Neurodegeneration. Handb Exp Pharmacol535–587.
10.
GalindoF, FloresA (2006) De la energética a la neurotransmisión: El adenosín trifosfato y sus receptores. Rev Neurol43, 667–677.
11.
FredholmBB, ChenJF, CunhaRA, SvenningssonP, VaugenoisJM (2005) Adenosine and brain function. Int Rev Neurobiol63, 191–240.
12.
Dall’IgnaOP, PorciúnculaLO, SouzaDO, CuhnaRA, LaraDR (2003) Neuroprotection by caffeine and adenosine A2A receptor blockade of β-amyloid neurotoxicity. Br J Pharmacol138, 1207–1209.
13.
KovácsZ, JuhászG, PalkovitsM, DovolyiA, KékesiK (2011) Area, age and gender of the nucleoside system in the brain: A review of current literature. Curr Top Med Chem11, 1012–1033.
UllrichC, PirchlM, HumpelC (2010) Hypercholesterolemia in rats impairs the cholinergic system and leads to memory deficits. Mol Cell Neurosci45, 408–417.
17.
RichterHS, ZeuchB, LankischK, GassP, DurstewitzD, VollmayrB (2013) Where have I been? Where should I go? Spatial working memory on a radial arm maze in a rat model of depression. Plos One8, 1–10.
18.
BurkeSN, RyanL, BarnesCA (2012) Characterizing cognitive aging of recognition memory and related processes in animal models and in humans. Front Aging Neurosci4, 1–13.
19.
LimWLF, MartinsIJ, MartinsRN (2014) The involvement of lipids in Alzheimer’s disease. J Genet Genomics41, 261–274.
20.
GranholmAC, Bimonte-NelsonHA, MooreAB, NelsonME, FreemanLR, SambamurtiK (2008) Effects of a saturated fat and high cholesterol diet on memory and hippocampal morphology in the middle-aged rat. J Alzheimers Dis14, 133–145.
21.
WoodWG, LiL, MüllerWE, EckertGP (2014) Cholesterol as a causative factor in Alzheimer disease: A debatable hypothesis. J Neurochem129, 559–572.
22.
HoshfieldLA, DaschilN, OräddG, StrömbergI, HumpelC (2014) Vascular pathology of 20-month-old hypercholesterolemia mice in comparison to triple-transgenic and APPSwDI Alzheimer’s disease mouse models. Mol Cell Neurosci63, 83–95.
OkerekeOI, RosnerBA, KimDH, KangJH, CookNR, MansonJE, BuringJE, WillettWC, GrodsteinF (2012) Dietary fat types and 4-year cognitive change in community-dwelling older women. Ann Neurol72, 124–134.
25.
SilversJM, HarrodSB, MactutusCF, BoozeRM (2007) Automation of the novel object recognition task for use in adolescent rats. J Neurosci Met166, 99–103.
26.
EspinosaJ, RochaA, NunesF, CostaMS, ScheinV, KazlauckasV, KalinineE, SouzaDO, CunhaRA, PorciúnculaLO (2013) Caffeine consumption prevents memory impairment, neuronal damage, and adenosine A2A receptors upregulation in the hippocampus of a rat model of sporadic dementia. J Alzheimers Dis34, 509–518.
PrasanthiJRP, SchragM, DasariB, MarwarhaG, KirschWM, GhribiO (2012) Deferiprone reduces amyloid-β and tau phosphorylation levels but not reactive oxygen species generation in hippocampus of rabbits fed a cholesterol-enriched diet. J Alzheimers Dis30, 167–182.
29.
ProitsiP, KimM, Whiley2L, PritchardM, LeungR, SoininenH, KloszewskaI, MecocciP, TsolakiM, VellasB, ShamP, LovestoneS, PowellJF, DobsonRJB, Legido-QuigleyC (2015) Plasma lipidomics analysis finds long chain cholesteryl esters to be associated with Alzheimer’s disease. Trans Psychiatry5, e494.
30.
Luque-ContrerasD, CarvajalK, Toral-RiosD, Franco-BocanegraD, Campos-PeñaV (2014) Oxidative stress and metabolic syndrome: Cause or consequence of Alzheimer’s disease?Oxid Med Cell Longev2014, 497802.
SperlághB, ViziES (2011) The role of extracellular adenosine in chemical neurotransmission in the hippocampus and basal ganglia: Pharmacological and clinical aspects. Curr Top Med Chem11, 1034–1046.
38.
CunhaRA (2005) Neuroprotection by adenosine in the brain: From A1 recetor activation to A2A receptor blockade. Purinergic Signal1, 111–134.
39.
JansenKLR, FaullRLM, DragunowM, SynekBL (1990) Alzheimer’s disease: Changes in hippocampal N-Methyl-D-aspartate, quisqualate, neurotensin, adenosine, benzodiazepine, serotonin and opioid receptors- an autoradiographic study. Neuroscience3, 613–627.
40.
FukumitsuN, IshiiK, KimuraY, OdaK, HashimotoM, SusukiM, IshiwataK (2008) Adenosine A(1) receptors using 8-dicyclopropylmethyl-1-[(11)C]methyl-3-propylxanthine PET in Alzheimer’s disease. Ann Nucl Med22, 841–847.
41.
von ArnimCAF, VerstegeE, EtrichSM, RiepeMW (2006) Mechanisms of hypoxic tolerance in presymptomatic APP23 transgenic mice. Mech Ageing Dev127, 109–114.
42.
Fernández-FernándezL, EstebanG, GiraltM, ValenteT, BoleaI, MontseS, PingS, BenítezS, MorellóJR, ReguantJ, RamírezB, HidalgoJ, UnzetaM (2015) Catecholaminergic and cholinergic systems of mouse brain are modulated by LMN diet, rich in theobromine, polyphenols and polyunsaturated fatty acids. Food Funct6, 1251–1260.
CouturierJ, StancuIC, SchakmanO, PierrotN, HuauxF, Kienlen-CampardP, DewachterI, OctaveJN (2016) Activation of phagocytic activity in astrocytes by reduced expression of the inflammasome component ASC and its implication in a mouse model of Alzheimer disease. J Neuroinflammation20, 1–13.
45.
SalminenA, OjalaJ, SuuronenT, KaarnirantaK, KauppinenA (2008) Amyloid-beta oligomers set fire to inflammasomes and induce Alzheimer’s pathology. J Cell Mol Med12, 2255–2262.
46.
LiuL, ChanC (2014) The role of inflammasome in Alzheimer’s disease. Ageing Res Rev15, 6–15.
