3,4-Methylenedioxymethamphetamine (MDMA) is still one of the most consumed drugs by adolescents. Its abuse is related with cognitive impairment, which seems due to maladaptive plasticity and neural stress. In turn, new hypotheses suggest that Alzheimer’s disease (AD) may be promoted by neural stressors.
Aims and methods:
To test if there is an increase in vulnerability to AD after chronic MDMA consumption, we investigated the effects of this drug on recognition memory and its neurotoxic and neuroplastic effects in a transgenic mouse model of presymptomatic familiar AD (APP/PS1 dE9, Tg).
Results:
MDMA-treated animals showed recognition memory deficits, regardless of genotype, which were accompanied by changes in plasticity markers. Tg mice showed an impaired expression of Arc compared with wild-type animals, but exposure to MDMA induced an increase in the expression of this factor of the same percentage in both genotypes. However, the expression of c-fos, BDNF and p-CREB was not significantly altered by MDMA treatment in Tg mice. Although Tg mice had higher free choline levels than wild-type mice (about 123%), MDMA did not modify these levels in any case, ruling out any specific effect of this drug on the acetylcholine pathway. MDMA treatment significantly increased the presence of cortical amyloid plaques, as well as Aβ40, Aβ42 and secreted APPβ levels in Tg mice. These plaques were accompanied by increased tau phosphorylation (S199), which does not seem to occur via the canonic pathway involving AKT, CDK5 or GSK3β.
Conclusions:
The present results support previous evidences that MDMA can contribute to the amyloid cascade.
AbadSCamarasaJPubillD, et al. (2016a) Adaptive plasticity in the hippocampus of young mice intermittently exposed to MDMA could be the origin of memory deficits. Mol Neurobiol53: 7271–7283.
2.
AbadSRamonCPubillD, et al. (2016b) Adolescent exposure to MDMA induces dopaminergic toxicity in substantia nigra and potentiates the amyloid plaque deposition in the striatum of APPswe/PS1dE9 mice. Biochim Biophys Acta1862: 1815–1826.
3.
AbadSFoleADel OlmoN, et al. (2014) MDMA enhances hippocampal-dependent learning and memory under restrictive conditions, and modifies hippocampal spine density. Psychopharmacology231: 863–874.
4.
AmbréeORichterHSachserN, et al. (2009) Levodopa ameliorates learning and memory deficits in a murine model of Alzheimer’s disease. Neurobiol Aging30: 1192–1204.
5.
AsoELomoioSLópez-GonzálezI, et al. (2012) Amyloid generation and dysfunctional immunoproteasome activation with disease progression in animal model of familial Alzheimer’s disease. Brain Pathol22: 636–653.
6.
AugustinackJCSandersJLTsaiLH, et al. (2002) Colocalization and fluorescence resonance energy transfer between cdk5 and AT8 suggests a close association in pre-neurofibrillary tangles and neurofibrillary tangles. J Neuropathol Exp Neurol61: 557–564.
7.
BenilovaIKarranEDe StrooperB (2012) The toxic Aβ oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci15: 349–357.
8.
Blurton-JonesMLaFerlaFM (2006) Pathways by which Abeta facilitates tau pathology. Curr Alzheimer Res3: 437–448.
9.
CamarasaJRodrigoTPubillD, et al. (2012) Memory impairment induced by amphetamine derivatives in laboratory animals and in humans: a review. Biomol Concepts3: 1–12.
10.
CamarasaJRosCPubillD, et al. (2010) Tumour necrosis factor alpha suppression by MDMA is mediated by peripheral heteromeric nicotinic receptors. Immunopharmacol Immunotoxicol32: 265–271.
11.
CarrollJCIbaMBangasserDA, et al. (2011) Chronic stress exacerbates tau pathology, neurodegeneration, and cognitive performance through a corticotropin-releasing factor receptor-dependent mechanism in a transgenic mouse model of tauopathy. J Neurosci31: 14436–14449.
12.
ChipanaCGarcía-RatésSCamarasaJ, et al. (2008) Different oxidative profile and nicotinic receptor interaction of amphetamine and 3,4-methylenedioxy-methamphetamine. Neurochem Int52: 401–410.
13.
ChomczynskiPSacchiN (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem162: 156–159.
14.
ColadoMIO’SheaEGreenAR (2004) Acute and long-term of MDMA on cerebral dopamine biochemistry and function. Psychopharmacology173: 249–263.
15.
ConnorTJConnellyDBKellyJP (2001) Methylenedioxymethamphetamine (MDMA; ‘Ecstasy’) suppresses antigen specific IgG2a and IFN-γ production. Immunol Lett78: 67–73.
16.
CostaGFrauLWardasJ, et al. (2013) MPTP-induced dopamine neuron degeneration and glia activation is potentiated in MDMA-pretreated mice. Mov Disord28: 1957–1965.
17.
de BragançaACMoreauRLMde BritoT, et al. (2017) Ecstasy induces reactive oxygen species, kidney water absorption and rhabdomyolysis in normal rats. Effect of N-acetylcysteine and allopurinol in oxidative stress and muscle fiber damage. PloS One12: e0179199.
18.
Duart-CastellsLLópez-ArnauRBuenrostro-JáureguiM, et al. (2019) Neuroadaptive changes and behavioral effects after a sensitization regime of MDPV. Neuropharmacology144: 271–281.
19.
FoxHMcLeanATurnerJ, et al. (2002) Neuropsychological evidence of a relatively selective profile of temporal dysfunction in drug-free MDMA (‘ecstasy’) polydrug users. Psychopharmacology162: 203–214.
20.
GoedertMCohenESJakesR, et al. (1992) p42 map kinase phosphorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A1Implications for Alzheimer’s disease. FEBS Lett312: 95–99.
21.
GranadoNEscobedoIO’SheaE, et al. (2008a) Early loss of dopaminergic terminals in striosomes after MDMA administration to mice. Synapse62: 80–84.
22.
GranadoNO’SheaEBoveJ, et al. (2008b) Persistent MDMA-induced dopaminergic neurotoxicity in the striatum and substantia nigra of mice. J Neurochem107: 1102–1112.
23.
GranadoNAres-SantosSMoratallaR (2014) D1 but not D4 dopamine receptors are critical for MDMA-induced neurotoxicity in mice. Neurotox Res25: 100–109.
24.
GranadoNAres-SantosSOlivaI, et al. (2011) Dopamine D2-receptor knockout mice are protected against dopaminergic neurotoxicity induced by methamphetamine or MDMA. Neurobiol Dis42: 391–403.
25.
Guzman-RamosKMoreno-CastillaPCastro-CruzM, et al. (2012) Restoration of dopamine release deficits during object recognition memory acquisition attenuates cognitive impairment in a triple transgenic mice model of Alzheimer’s disease. Learn Mem19: 453–460.
26.
HalpinLECollinsSAYamamotoBK (2014) Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine. Life Sci97: 37–44.
27.
HammondRSTullLEStackmanRW (2004) On the delay-dependent involvement of the hippocampus in object recognition memory. Neurobiol Learn Mem82: 26–34.
28.
HardyJSelkoeDJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science297: 353–356.
29.
HeJQiaoJPZhuS, et al. (2013) Serum beta-amyloid peptide levels spike in the early stage of Alzheimer-like plaque pathology in an APP/PS1 double transgenic mouse model. Curr Alzheimer Res10: 979–986.
30.
HoughtonPJHowesMJ (2005) Natural products and derivatives affecting neurotransmission relevant to Alzheimer’s and Parkinson’s disease. Neurosignals14: 6–22.
31.
IshiiTHagaS (1976) Immuno-electron microscopic localization of immunoglobulins in amyloid fibrils of senile plaques. Acta Neuropathol36: 243–249.
32.
Jarosz-GriffithsHHNobleERushworthJV, et al. (2016) Amyloid-β receptors: the good, the bad, and the prion protein. J Biol Chem291: 3174–3183.
33.
KálmánJBjelikAHugyeczM, et al. (2007) 3,4-Methylenedioxymethamphetamine (MDMA), but not morphine, alters APP processing in the rat brain. Int J Neuropsychopharmacol10: 183–190.
34.
KilkennyCBrowneWCuthillIC, et al. (2010) Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol160: 1577–1579.
35.
Koenigsknecht-TalbooJLandrethGE (2005) Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J Neurosci25: 8240–8249.
36.
LeeEBSkovronskyDMAbtahianF, et al. (2003) Secretion and intracellular generation of truncated Abeta in beta-site amyloid-beta precursor protein-cleaving enzyme expressing human neurons. J Biol Chem278: 4458–4466.
37.
LiNLiuG (2010) The novel squamosamide derivative FLZ enhances BDNF/TrkB/CREB signaling and inhibits neuronal apoptosis in APP/PS1 mice. Acta Pharmacol Sin31: 265–272.
38.
MontgomeryCHattonNPFiskJE, et al. (2010) Assessing the functional significance of ecstasy-related memory deficits using a virtual paradigm. Hum Psychopharmacol25: 318–325.
39.
MoratallaRKhairnarASimolaN, et al. (2017) Amphetamine-related drugs neurotoxicity in humans and in experimental animals: main mechanisms. Prog Neurobiol155: 149–170.
40.
MravecBHorvathovaLPadovaA (2018) Brain under stress and Alzheimer’s disease. Cell Mol Neurobiol38: 73–84.
41.
Nava-MesaMOJiménez-DíazLYajeyaJ, et al. (2014) GABAergic neurotransmission and new strategies of neuromodulation to compensate synaptic dysfunction in early stages of Alzheimer’s disease. Front Cell Neurosci8: 167.
42.
O’CallaghanJPMillerDB (1994) Neurotoxicity profiles of substituted amphetamines in the C57BL/6J mouse. J Pharmacol Exp Ther270: 741–751.
43.
OddoSVasilevkoVCaccamoA, et al. (2006) Reduction of soluble Abeta and tau, but not soluble Abeta alone, ameliorates cognitive decline in transgenic mice with plaques and tangles. J Biol Chem281: 39413–39423.
44.
OtthCConchaIIArendtT, et al. (2002) AβPP induces cdk5-dependent tau hyperphosphorylation in transgenic mice Tg2576. J Alzheimers Dis4: 417–430.
45.
PalopJJMuckeL (2016) Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat Rev Neurosci17: 777–792.
46.
PerezSELazarovOKoprichJB, et al. (2005) Nigrostriatal dysfunction in familial Alzheimer’s disease-linked APPswe/PS1DeltaE9 transgenic mice. J Neurosci25: 10220–10229.
47.
PerryEKTomlinsonBEBlessedG, et al. (1978) Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J2: 1457–1459.
48.
ReveronMEMonksTJDuvauchelleCL (2005) Age-dependent (+)MDMA-mediated neurotoxicity in mice. NeuroToxicology26: 1031–1040.
49.
RudnickGWallSC (1992) The molecular mechanism of ‘ecstasy’ [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Proc Natl Acad Sci USA89: 1817–1821.
50.
RussoSJDietzDMDumitriuD, et al. (2010) The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends Neurosci33: 267–276.
51.
SanchezVCamareroJO’SheaE, et al. (2003) Differential effect of dietary selenium on the long-term neurotoxicity induced by MDMA in mice and rats. Neuropharmacology44: 449–461.
52.
SelenicaMLBBrownlowMJimenezJP, et al. (2013) Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy. Neurodegener Dis11: 165–181.
53.
ShankarGMLiSMehtaTH, et al. (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med14: 837–842.
54.
SkeltonMRWilliamsMTVorheesCV (2006) Treatment with MDMA from P11–20 disrupts spatial learning and path integration learning in adolescent rats but only spatial learning in older rats. Psychopharmacology189: 307–318.
55.
Sturchler-PierratCAbramowskiDDukeM, et al. (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA94: 13287–1392.
56.
SunJRoyS (2018) The physical approximation of APP and BACE-1: a key event in Alzheimer’s disease pathogenesis. Dev Neurobiol78: 340–347.
57.
SuzukiTNakayaT (2008) Regulation of amyloid beta-protein precursor by phosphorylation and protein interactions. J Biol Chem283: 29633–29637.
58.
TamagnoERobinoGObbiliA, et al. (2003) H2O2 and 4-hydroxynonenal mediate amyloid beta-induced neuronal apoptosis by activating JNKs and p38MAPK. Exp Neurol180: 144–155.
59.
TamayevRZhouDD’AdamioL (2009) The interactome of the amyloid β precursor protein family members is shaped by phosphorylation of their intracellular domains. Mol Neurodegener4: 28.
60.
TerryAVBuccafuscoJJ (2003) The cholinergic hypothesis of age and Alzheimer’s disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther306: 821–827.
61.
TongLBalazsRThorntonPL, et al. (2004) Beta-amyloid peptide at sublethal concentrations downregulates brain-derived neurotrophic factor functions in cultured cortical neurons. J Neurosci24: 6799–6809.
62.
TrigoJMCabrero-CastelABerrenderoF, et al. (2008) MDMA modifies active avoidance learning and recall in mice. Psychopharmacology197: 391–400.
63.
UjikeHTakakiMKodamaM, et al. (2002) Gene expression related to synaptogenesis, neuritogenesis, and MAP kinase in behavioral sensitization to psychostimulants. Ann NY Acad Sci965: 55–67.
64.
ValenteMJBastosMLFernandesE, et al. (2017) Neurotoxicity of β-keto amphetamines: deathly mechanisms elicited by methylone and MDPV in human dopaminergic SH-SY5Y cells. ACS Chem Neurosci8: 850–859.
65.
ViolaKLKleinWL (2015) Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol129: 183–206.
66.
WhiteSRObradovicTImelKM, et al. (1996) The effects of methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) on monoaminergic neurotransmission in the central nervous system. Prog Neurobiol49: 455–479.
67.
WhitehousePJPriceDLClarkAW, et al. (1981) Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol10: 122–126.
68.
WirthsOMulthaupGCzechC, et al. (2001) Intraneuronal Aβ accumulation precedes plaque formation in β-amyloid precursor protein and presenilin-1 double-transgenic mice. Neurosci Lett306: 116–120.
69.
WunderliMDVonmoosMFürstM, et al. (2017) Discrete memory impairments in largely pure chronic users of MDMA. Eur Neuropsychopharmacol27: 987–999.
70.
XieHHouSJiangJ, et al. (2013) Rapid cell death is preceded by amyloid plaque-mediated oxidative stress. Proc Natl Acad Sci USA110: 7904–7909.
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