The Ethyl Acetate Extract of Leaves of Ugni molinae Turcz. Improves Neuropathological Hallmarks of Alzheimer’s Disease in Female APPswe/PS1dE9 Mice Fed with a High Fat Diet
Restricted accessResearch articleFirst published online November 23, 2018
The Ethyl Acetate Extract of Leaves of Ugni molinae Turcz. Improves Neuropathological Hallmarks of Alzheimer’s Disease in Female APPswe/PS1dE9 Mice Fed with a High Fat Diet
The most common type of dementia is Alzheimer’s disease (AD), a progressive neurodegenerative disease characterized by impairment in cognitive performance in aged individuals. Currently, there is no effective pharmacological treatment that cures the disease due to the lack of knowledge on the actual mechanisms involved in its pathogenesis. In the last decades, the amyloidogenic hypothesis has been the most studied theory trying to explain the origin of AD, yet it does not address all the concerns relating to its development. In the present study, a possible new preclinical treatment of AD was evaluated using the ethyl acetate extract (EAE) of leaves of Ugni molinae Turcz. (synonym Myrtus ugni Molina Family Myrtacea). The effects were assessed on female transgenic mice from a preclinical model of familial AD (APPswe/PS1dE9) combined with a high fat diet. This preclinical model was selected due to the already available experimental and observational data proving the relationship between obesity, gender, metabolic stress, and cognitive dysfunction; related to characteristics of sporadic AD. According to chemical analyses, EAE would contain polyphenols such as tannins, flavonoid derivatives, and phenolic acids, as well as pentacyclic triterpenoids that exhibit neuroprotective, anti-inflammatory, and antioxidant effects. In addition, the treatment evidenced its capacity to prevent deterioration of memory capacity and reduction of progression speed of AD neuropathology.
JahnH (2013) Memory loss in Alzheimer’s disease. Dialogues ClinNeurosci15, 445–454.
5.
QuerfurthHW, LaFerlaFM (2010) Alzheimer’s disease. N Engl J Med362, 329–344.
6.
YiannopoulouKG, PapageorgiouSG (2013) Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord6, 19–33.
7.
ChneiderLS, MangialascheF, AndreasenN, FeldmanH, GiacobiniE, JonesR, MantuaV, MecocciP, PaniL, WinbladB, KivipeltoM (2014) Clinical trials and late-stage drug development for Alzheimer’s disease: An appraisal from 1984 to 2014. J Intern Med275, 251–283.
8.
CummingsJ, LeeG, MortsdorfT, RitterA, ZhongK (2017) Alzheimer’s disease drug development pipeline: 2017. Alzheimers Dement (N Y)3, 367–384.
Wyss-CorayT, RogersJ (2012) Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med2, a006346.
ZhuS, WangJ, ZhangY, HeJ, KongJ, WangJF, LiXM (2017) The role of neuroinflammation and amyloid in cognitive impairment in an APP/PS1 transgenic mouse model of Alzheimer’s disease. CNS Neurosci Ther23, 310–320.
19.
CifuentesD, PoittevinM, DereE, Broquères-YouD, BonninP, BenessianoJ, PocardM, MarianiJ, KubisN, Merkulova-RainonT, LévyBI (2015) Hypertension accelerates the progression of Alzheimer-like pathology in a mouse model of the disease. Hypertension65, 218–224.
20.
KalariaRN, MaestreGE, ArizagaR, FriedlandRP, GalaskoD, HallK, LuchsingerJA, OgunniyiA, PerryEK, PotocnikF, PrinceM, StewartR, WimoA, ZhangZX, AntuonoP, World Federation of Neurology Dementia Research Group (2008) Alzheimer’s disease and vascular dementiain developing countries: Prevalence, management, and risk factors. Lancet Neurol7, 812–826.
21.
JansonJ, LaedtkeT, ParisiJE, O'BrienP, PetersenRC, ButlerPC (2004) Increased risk of type 2 diabetes in Alzheimer disease. Diabetes, 53, 474–481.
22.
ReitzC (2013) Dyslipidemia and the risk of Alzheimer’s Disease. Curr Atheroscler Rep15, 1–14.
23.
Vanhanen, M., Koivisto, K, MoilanenL, HelkalaEL, HanninenT, SoininenH, KervinenK, KesäniemiYA, LaaksoM, KuusistoJ (2006) Association of metabolic syndrome with Alzheimer disease: A population-based study. Neurology67, 843–847.
24.
AguirreMC, DelporteC, BackhouseN, ErazoS, Letel ierME, CasselsBK, SilvaX, AlegríaS, NegreteR (2006) Topical anti-inflammatory activity of 2 alpha-hydroxy pentacyclic triterpene acids from the leaves of Ugni molinae. Bioorg Med Chem14, 5673–5677.
25.
Peña-CerdaM, Arancibia-RadichJ, Valenzuela-BustamanteP, Pérez-ArancibiaR, BarrigaA, SeguelI, GarcíaL, DelporteC (2017) Phenolic composition and antioxidant capacity of Ugni molinae Turcz. leaves of different genotypes. Food Chem215, 219–227.
26.
DelporteC, BackhouseN, InostrozaV, AguirreMC, PeredoN, SilvaX, NegreteR, MirandaHF (2007) Analgesic activity of Ugni molinae (murtilla) in mice models of acute pain. J Ethnopharmacol112, 162–165.
27.
RubilarM, PineloM, Ihl, M, ScheuermannE, SineiroJ, NunezMJ (2006) Murta leaves (Ugni molinae Turcz) as a source of antioxidant polyphenols. J Agr Food Chem54, 59–64.
28.
GoityL, QueupilMJ, JaraD, AlegriaMSP, BarrigaA, AguirreMC, DelporteC (2013) An HPLC-UV and HPLC-ESLMS based method for identification of antiinflammatory triterpenoids from the extracts of Ugni molinae. Bol Latinoam Caribe Plantas Med Aromat12, 108–116.
29.
ZhangS, ChaiR, YangYY, GuoSQ, WangS, GuoT, XuSF, ZhangYH, WangZY, GuoC (2017) Chronic diabetic states worsen Alzheimer neuropathology and cognitive deficits accompanying disruption of calcium signaling in leptin-deficient APP/PS1 mice. Oncotarget8, 43617–43634.
30.
RuizHH, ChiT, ShinAC, LindtnerC, HsiehW, EhrlichM, GandyS, BuettnerC (2016) Increased susceptibility to metabolic dysregulation in a mouse model of Alzheimer’s disease is associated with impaired hypothalamic insulin signaling and elevated BCAA levels. Alzheimers Dement12, 851–861.
31.
Ramos-RodriguezJJ, Spires-JonesT, PoolerAM, Lechuga-SanchoAM, BacskaiBJ, Garcia-AllozaM (2017) Progressive neuronal pathology and synaptic loss induced by prediabetes and type 2 diabetes in a mouse model of Alzheimer’s disease. Mol Neurobiol54, 3428–3438.
32.
JiaoSS, BuXL, LiuYH, ZhuC, WangQH, ShenLL, LiuCH, WangYR, YaoXQ, WangYJ (2016) Sex dimorphism profile of Alzheimer’s disease-type pathologies in an APP/PS1 mouse model. Neurotox Res29, 256–266.
33.
LiX, FengY, WuW, ZhaoJ, FuC, LiY, DingY, WuB, GongY, YangG, ZhouX (2016) Sex differences between APPswePS1dE9 mice in A-beta accumulation and pancreatic islet function during the development of Alzheimer’s disease. Lab Anim50, 275–285.
34.
EnnaceurA, NeaveN, AggletonJP (1997) Spontaneous object recognition and object location memory in rats: The effects of lesions in the cingulate cortices, the medial prefrontal cortex, the cingulum bundle and the fornix. Exp Brain Res113, 509–519.
35.
Michodjehoun-MestresL1, AmraouiW, BrillouetJM (2009) Isolation, characterization, and determination of 1-O-trans-cinnamoyl-beta-D-glucopyranose in the epidermis and flesh of developing cashew apple (Anacardium occidentale L.) and four of its genotypes. JAgric Food Chem57,1377–1382.
36.
PaxinosG, WatsonC (1986) The Rat Brain in Stereotaxic Coordinates, Academic Press, Sydney.
37.
De LemosL, JunyentF, CaminsA, Castro-TorresRD, FolchJ, OlloquequiJ, Beas-ZarateC, VerdaguerE, AuladellC (2018) Neuroprotective effects of the absence of JNK1 or JNK3 isoforms on kainic acid-induced temporal lobe epilepsy-like symptoms. Mol Neurobiol55, 4437–4452.
38.
StohsSJ, MillerH, KaatsGR (2012) A review of the efficacy and safety of banaba (Lagerstroemia speciosa L.) and corosolic acid. PhytRes26, 317–324.
39.
MolinoS, DossenaM, BuonocoreD, FerrariF, VenturiniL, RicevutiG, VerriM (2016) Polyphenols in dementia: From molecular basis to clinical trials. Life Sci161, 69–77.
40.
KajdzanoskaM, PetreskaJ, StefovaM (2011) Comparison of different extraction solvent mixtures for characterization of phenolic compounds in strawberries. J Agr Food Chem59, 5272–5278.
41.
BhullarKS, RupasingheHP (2013) Polyphenols: Multipotent therapeutic agents in neurodegenerative diseases. Oxid Med Cell Longev2013, 891748.
42.
VauzourD (2012) Dietary polyphenols as modulators of brain functions: Biological actions and molecular mechanisms underpinning their beneficial effects. Oxid Med Cell Longev2012,914273.
43.
McDadeE, BatemanRJ (2017) Stop Alzheimer’s before it starts. Nature547, 153–155.
PeknyM, WilhelmssonU, PeknaM (2014) The dual role of astrocyte activation and reactive gliosis. Neurosci Lett565, 30–38.
46.
MosherKI, Wyss-CorayT (2014) Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem Pharmacol88, 594–604.
47.
EttchetoM, PetrovD, PedrósI, AlvaN, CarbonellT, Beas-ZarateC, PallasM, AuladellC, FolchJ, CaminsA (2016) Evaluation of neuropathological effects of a high-fat diet in a presymptomatic Alzheimer’s disease stage in APP/PS1 mice. J Alzheimers Dis54, 233–251.
48.
PetrovD, PedrósI, ArtiachG, SuredaFX, BarrosoE, PallasM, AuladellC, FolchJ, CaminsA (2015) High-fat diet-induced deregulation of hippocampal insulin signaling and mitochondrial homeostasis deficiencies contribute to Alzheimer disease pathology in rodents. Biochem Biophys Acta1852, 1687–1699.
49.
FragoulisA, SieglS, FendtM, JansenS, SoppaU, BrandenburgLO, WruckCJ (2017) Oral administration of methysticin improves cognitive deficits in a mouse model of Alzheimer’s disease. Redox Biol12, 843–853.
50.
ManiV, JaafarS M, AzahanNSM, RamasamyK, LimSM, MingL C, MajeedABA (2017) Ciproxifan improves cholinergic transmission, attenuates neuroinflammation and oxidative stress but does not reduce amyloid level in trans-genic mice. Life Sci180, 23–35.
51.
MoriT, KoyamaN, TanJ, SegawaT, MaedaM, TownT (2017) Combination therapy with octyl gallate and ferulic acid improves cognition and neurodegeneration in a trans-genic mouse model of Alzheimer disease. J Biol Chem292, 11310–11325.
52.
McGeerPL, GuoJP, LeeM, KennedyK, McGeerEG (2018) Alzheimer’s disease can be spared by nonsteroidal anti-inflammatory drugs. J Alzheimers Dis62, 1219–1222.
53.
MorrisonJH, BaxterMG (2012) The ageing cortical synapse: Hallmarks and implications for cognitive decline. Nat Rev Neurosci13, 240–250.
54.
KrauseDL, MüllerN (2010) Neuroinflammation, microglia and implications for anti-inflammatory treatment in Alzheimer’s disease. Int J Alzheimers Dis2010, 73280.
55.
BecherA, DrenckhahnA, PahnerI, MargittaiM, JahnR, Ahnert-HilgerG (1999) The synaptophysin-synaptobrevin complex: A hallmark of synaptic vesicle maturation. J Neu-rosci19, 1922–1931.
56.
ZhangW, HaoJ, LiuR, ZhangZ, LeiG, SuC, MiaoJ, LiZ (2011) Soluble Aß levels correlate with cognitive deficits in the 12-month-old APPswe/PS1dE9 mouse model of Alzheimer’s disease. Behav Brain Res222, 342–350.
57.
JankowskyJL, ZhengH (2017) Practical considerations for choosing a mouse model of Alzheimer’s disease. Mol Neurodegener12, 89.
58.
BanJY, NguyenHTT, LeeHJ, ChoSO, JuHS, KimJY, SeongYH (2008) Neuroprotective properties of gallic acid from Sanguisorbae radix on amyloid beta protein (25-35)-induced toxicity in cultured rat cortical neurons. Biol Pharmaceut Bull31, 149–153.
59.
ChoiY, KimTD, PaikSR, JeongK, JungS (2008) Molecular simulations for anti-amyloidogenic effect of flavonoid myricetin exerted against Alzheimer’s ß-amyloid fibrils formation. Bull Korean Chem Soc29, 1505–1509.
60.
CuevasE, LimónD, Pérez-SeverianoF, DíazA, OrtegaL, ZentenoE, GuevaraJ (2009) Antioxidant effects of epicat-echin on the hippocampal toxicity caused by amyloid-beta 25-35 in rats. Eur J Pharmacol616, 122–127.
61.
MurphyMP, LeVineH (2010) Alzheimer’s disease and the amyloid-P peptide. J Alzheimers Dis19, 311–323.
62.
ReF, AiroldiC, ZonaC, MasseriniM, FerlaB L, QuattrocchiN, NicotraF (2010) Beta amyloid aggregation inhibitors: Small molecules as candidate drugs for therapy of Alzheimer’s disease. CurrMed Chem17, 2990–3006.
63.
RoherA, WolfeD, PalutkeM, KuKurugaD (1986) Purification, ultrastructure, and chemical analysis of Alzheimer disease amyloid plaque core protein. Proc Nat Acad Sci USA83, 2662–2666.
64.
TorokB, BagS, SarkarM, DasguptaS, TorokM (2013) Structural features of small molecule amyloid-beta self-assembly inhibitors. Curr Bioact Com9, 37–63.
65.
ZhaoJ, O'ConnorT, VassarR (2011) The contribution of activated astrocytes to Aβ production: Implications for Alzheimer’s disease pathogenesis. J Neuroinflammation8, 150.
66.
FioriJ, NaldiM, BartoliniM, AndrisanoV (2012) Disclosure of a fundamental clue for the elucidation of the myricetin mechanism of action as amyloid aggregation inhibitor by mass spectrometry. Electrophoresis33, 3380–3386.
67.
OnoK, YoshiikeY, TakashimaA, HasegawaK, NaikiH, YamadaM (2003) Potent anti - amyloidogenic and fibril - destabilizing effects of polyphenols in vitro: Implications for the prevention and therapeutics of Alzheimer’s disease. J Neurochem87, 172–181.
68.
Jiménez-AliagaK, Bermejo-BescósP, BenedíJ, Martín-AragónS (2011) Quercetin and rutin exhibit antiamy-loidogenic and fibril-disaggregating effects in vitro and potent antioxidant activity in APPswe cells. Life Sci89,
69.
PlanchardMS, SamelMA, KumarA, RangachariV (2012) The natural product betulinic acid rapidly promotes amyloid-p fibril formation at the expense of soluble oligomers. ACS Chem Neurosci3, 900–908.
70.
PoratY, AbramowitzA, GazitE (2006) Inhibition of amyloid fibril formation by polyphenols: Structural similarity and aromatic interactions as a common inhibition mechanism. Chem Biol Drug Des67, 27–37.
71.
SyllaT, PouységuL, Da CostaG, DeffieuxD, MontiJP, QuideauS (2015) Gallotannins and tannic acid: First chemical syntheses and in vitro inhibitory activity on Alzheimer’s amyloid β-peptide aggregation. Angew Chem127, 8335–8339.
72.
HongSY, JeongWS, JunM (2012) Protective effects of the key compounds isolated from Corni fructus against β-amyloid-induced neurotoxicity in PC12 cells. Molecules17, 10831–10845.
73.
KimH, ParkBS, LeeKG, ChoiCY, JangSS, KimYH, LeeSE (2005) Effects of naturally occurring compounds on fibril formation and oxidative stress of β-amyloid. J Agr Food Chem53, 8537–8541.
74.
OliveiraMR (2016) The effects of ellagic acid upon brain cells: A mechanistic view and future directions. Neurochem Res41, 1219–1228.
75.
GuimaraesCC, OliveiraDD, ValdeviteM, SaltorattoAL, Pereira, SLV, de Castro FrancaS, PereiraPS (2015) The glycosylated flavonoids vitexin, isovitexin, and quercetrin isolated from Serjania erecta Radlk (Sapindaceae) leaves protect PC12 cells against amyloid-β 25-35 peptide-induced toxicity. Food Chem Toxicol86, 88–bor94.
76.
HeoHJ, LeeCY (2005) Epicatechin and catechin in cocoa inhibit amyloid p protein induced apoptosis. J Agr Food Chem53, 1445–1448.
