Brain amyloid-β (Aβ) peptide is released into the interstitial fluid (ISF) in a neuronal activity-dependent manner, and Aβ deposition in Alzheimer’s disease (AD) is linked to baseline neuronal activity. Although the intrinsic mechanism for Aβ generation remains to be elucidated, interleukin-like epithelial-mesenchymal transition inducer (ILEI) is a candidate for an endogenous Aβ suppressor.
Objective:
This study aimed to access the mechanism underlying ILEI secretion and its effect on Aβ production in the brain.
Methods:
ILEI and Aβ levels in the cerebral cortex were monitored using a newly developed ILEI-specific ELISA and in vivo microdialysis in mutant human Aβ precursor protein-knockin mice. ILEI levels in autopsied brains and cerebrospinal fluid (CSF) were measured using ELISA.
Results:
Extracellular release of ILEI and Aβ was dependent on neuronal activation and specifically on tetanus toxin-sensitive exocytosis of synaptic vesicles. However, simultaneous monitoring of extracellular ILEI and Aβ revealed that a spontaneous fluctuation of ILEI levels appeared to inversely mirror that of Aβ levels. Selective activation and inhibition of synaptic receptors differentially altered these levels. The evoked activation of AMPA-type receptors resulted in opposing changes to ILEI and Aβ levels. Brain ILEI levels were selectively decreased in AD. CSF ILEI concentration correlated with that of Aβ and were reduced in AD and mild cognitive impairment.
Conclusion:
ILEI and Aβ are released from distinct subpopulations of synaptic terminals in an activity-dependent manner, and ILEI negatively regulates Aβ production in specific synapse types. CSF ILEI might represent a surrogate marker for the accumulation of brain Aβ.
ChaudhuryA, HusseyGS, RayPS, JinG, FoxPL, HowePH (2010) TGF-β-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI. Nat Cell Biol12, 286–293.
2.
LahsnigC, MikulaM, PetzM, ZulehnerG, SchnellerD, van ZijlF, HuberH, CsiszarA, BeugH, MikulitsW (2009) ILEI requires oncogenic Ras for the epithelial to mesenchymal transition of hepatocytes and liver carcinoma progression. Oncogene28, 638–650.
3.
MackenzieNC, RazE (2006) Found in translation: A new player in EMT. Dev Cell11, 434–436.
4.
MauriP, ScarpaA, NascimbeniAC, BenazziL, ParmagnaniE, MafficiniA, Della PerutaM, BassiC, MiyazakiK, SorioC (2005) Identification of proteins released by pancreatic cancer cells by multidimensional protein identification technology: A strategy for identification of novel cancer markers. FASEB J19, 1125–1127.
5.
WaernerT, AlacakaptanM, TamirI, OberauerR, GalA, BrabletzT, SchreiberM, JechlingerM, BeugH (2006) ILEI: A cytokine essential for EMT, tumor formation, and late events in metastasis in epithelial cells.. Cancer Cell10, 227–239.
6.
MaattaJA, BendreA, LaantiM, BukiKG, RantakariP, TervolaP, SaarimakiJ, PoutanenM, HarkonenP, VaananenK (2016) Fam3c modulates osteogenic cell differentiation and affects bone volume and cortical bone mineral density. Bonekey Rep5, 787.
LiuL, WatanabeN, AkatsuH, NishimuraM (2016) Neuronal expression of ILEI/FAM3C and its reduction in Alzheimer’s disease. Neuroscience330, 236–246.
16.
SaitoT, MatsubaY, MihiraN, TakanoJ, NilssonP, ItoharaS, IwataN, SaidoTC (2014) Single App knock-in mouse models of Alzheimer’s disease. Nat Neurosci17, 661–663.
17.
TakedaS, SatoN, IkimuraK, NishinoH, RakugiH, MorishitaR (2011) Novel microdialysis method to assess neuropeptides and large molecules in free-moving mouse. Neuroscience186, 110–119.
18.
JanssonAM, CsiszarA, MaierJ, NystromAC, AxE, JohanssonP, SchiavoneLH (2017) The interleukin-like epithelial-mesenchymal transition inducer ILEI exhibits a non-interleukin-like fold and is active as a domain-swapped dimer. J Biol Chem292, 15501–15511.
19.
KangJE, LimMM, BatemanRJ, LeeJJ, SmythLP, CirritoJR, FujikiN, NishinoS, HoltzmanDM (2009) Amyloid-β dynamics are regulated by orexin and the sleep-wake cycle. Science326, 1005–1007.
20.
CirritoJR, MayPC, O’DellMA, TaylorJW, ParsadanianM, CramerJW, AudiaJE, NissenJS, BalesKR, PaulSM, DeMattosRB, HoltzmanDM (2003) In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-β metabolism and half-life. J Neurosci23, 8844–8853.
21.
HettingerJC, LeeH, BuG, HoltzmanDM, CirritoJR (2018) AMPA-ergic regulation of amyloid-β levels in an Alzheimer’s disease mouse model. Mol Neurodegener13, 22.
22.
WhittonPS, MaioneS, BiggsCS, FowlerLJ (1994) Tonic desensitization of hippocampal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors regulates 5-hydroxytryptamine release in vivo. Neuroscience63, 945–948.
23.
VergesDK, RestivoJL, GoebelWD, HoltzmanDM, CirritoJR (2011) Opposing synaptic regulation of amyloid-β metabolism by NMDA receptors in vivo. J Neurosci31, 11328–11337.
24.
BeachTG, KuoYM, SchwabC, WalkerDG, RoherAE (2001) Reduction of cortical amyloid β levels in guinea pig brain after systemic administration of physostigmine. Neurosci Lett310, 21–24.
25.
CaccamoA, OddoS, BillingsLM, GreenKN, Martinez-CoriaH, FisherA, LaFerlaFM (2006) M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron49, 671–682.
26.
SomogyiP, TamasG, LujanR, BuhlEH (1998) Salient features of synaptic organisation in the cerebral cortex. Brain Res Brain Res Rev26, 113–135.
27.
PicciottoMR, HigleyMJ, MineurYS (2012) Acetylcholine as a neuromodulator: Cholinergic signaling shapes nervous system function and behavior. Neuron76, 116–129.
28.
SauraCA, ChenG, MalkaniS, ChoiSY, TakahashiRH, ZhangD, GourasGK, KirkwoodA, MorrisRG, ShenJ (2005) Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice. J Neurosci25, 6755–6764.
29.
WillenK, SrokaA, TakahashiRH, GourasGK (2017) Heterogeneous association of Alzheimer’s disease-linked amyloid-β and amyloid-β protein precursor with synapses. J Alzheimers Dis60, 511–524.
30.
HalffAW, Gomez-VarelaD, JohnD, BergDK (2014) A novel mechanism for nicotinic potentiation of glutamatergic synapses. J Neurosci34, 2051–2064.
31.
KoukouliF, RooyM, ChangeuxJP, MaskosU (2016) Nicotinic receptors in mouse prefrontal cortex modulate ultraslow fluctuations related to conscious processing. Proc Natl Acad Sci U S A113, 14823–14828.
32.
RiceHC, MarcassaG, ChrysidouI, HorreK, Young-PearseTL, MullerUC, SaitoT, SaidoTC, VassarR, de WitJ, De StrooperB (2020) Contribution of GABAergic interneurons to amyloid-β plaque pathology in an APP knock-in mouse model. Mol Neurodegener15, 3.
33.
RodriguesDI, GutierresJ, PliassovaA, OliveiraCR, CunhaRA, AgostinhoP (2014) Synaptic and sub-synaptic localization of amyloid-β protein precursor in the rat hippocampus. J Alzheimers Dis40, 981–992.
34.
NordbergA, Hellstrom-LindahlE, LeeM, JohnsonM, MousaviM, HallR, PerryE, BednarI, CourtJ (2002) Chronic nicotine treatment reduces β-amyloidosis in the brain of a mouse model of Alzheimer’s disease (APPsw). J Neurochem81, 655–658.
LassekM, WeingartenJ, EinsfelderU, BrendelP, MullerU, VolknandtW (2013) Amyloid precursor proteins are constituents of the presynaptic active zone. J Neurochem127, 48–56.
37.
LudewigS, KorteM (2016) Novel insights into the physiological function of the APP (gene) family and its proteolytic fragments in synaptic plasticity. Front Mol Neurosci9, 161.
38.
BarthetG, Jorda-SiquierT, Rumi-MasanteJ, BernadouF, MullerU, MulleC (2018) Presenilin-mediated cleavage of APP regulates synaptotagmin-7 and presynaptic plasticity. Nat Commun9, 4780.
