Alzheimer’s disease (AD) is an age-related neurodegenerative disorder with multifactorial etiopathogenesis, characterized by progressive loss of memory and other cognitive functions. A fundamental neuropathological feature of AD is the early and severe brain cholinergic neurodegeneration. Lithium is a monovalent cation classically utilized in the treatment of mood disorders, but recent evidence also advances a beneficial potentiality of this compound in neurodegeneration. Interestingly, lithium acts on several processes whose alterations characterize the brain cholinergic impairment at short and long term. On this basis, the aim of the present research was to evaluate the potential beneficial effects of a chronic lithium treatment in preventing the damage that a basal forebrain cholinergic neurodegeneration provokes, by investigating memory functions and neurodegeneration correlates. Adult male rats were lesioned by bilateral injections of the immunotoxin 192 IgG-Saporin into the basal forebrain. Starting 7 days before the surgery, the animals were exposed to a 30-day lithium treatment, consisting of a 0.24% Li2CO3 diet. Memory functions were investigated by the open field test with objects, the sociability and preference for social novelty test, and the Morris water maze. Hippocampal and neocortical choline acetyltransferase (ChAT) levels and caspase-3 activity were determined. Cholinergic depletion significantly impaired spatial and social recognition memory, decreased hippocampal and neocortical ChAT levels and increased caspase-3 activity. The chronic lithium treatment significantly rescued memory performances but did not modulate ChAT availability and caspase-3 activity. The present findings support the lithium protective effects against the cognitive impairment that characterizes the brain cholinergic depletion.
HoltzmanDM, MorrisJC, GoateAM (2011) Alzheimer’s disease: The challenge of the second century. Sci Transl Med3, 77sr1.
2.
Alzheimer’s Association (2015) Alzheimer’s disease facts and figures. Alzheimers Dement11, 332–384.
3.
PrinceM, BryceR, AlbaneseE, WimoA, RibeiroW, FerriCP (2013) The global prevalence of dementia: A systematic review and metaanalysis. Alzheimers Dement9, 63–75.e2.
4.
MangialascheF, SolomonA, WinbladB, MecocciP, KivipeltoM (2010) Alzheimer’s disease: Clinical trials and drug development. Lancet Neurol9, 702–716.
5.
ChuLW (2012) Alzheimer’s disease: Early diagnosis and treatment. Hong Kong Med J18, 228–237.
6.
HuangY, MuckeL (2012) Alzheimer mechanisms and therapeutic strategies. Cell148, 1204–1222.
7.
BartusRT (2000) On neurodegenerative diseases, models, and treatment strategies: Lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp Neurol163, 495–529.
8.
HärtigW, SaulA, KaczaJ, GroscheJ, GoldhammerS, MichalskiD, WirthsO (2014) Immunolesion-induced loss of cholinergic projection neurones promotes β-amyloidosis and tau hyperphosphorylation in the hippocampus of triple-transgenic mice. Neuropathol Appl Neurobiol40, 106–120.
9.
YoungW (2009) Review of lithium effects on brain and blood. Cell Transplant18, 951–975.
10.
OruchR, ElderbiMA, KhattabHA, PrymeIF, LundA (2014) Lithium: A review of pharmacology, clinical uses, and toxicity. Eur J Pharmacol740, 464–473.
11.
CaminsA, VerdaguerE, JunyentF, Yeste-VelascoM, PelegríC, VilaplanaJ, PallásM (2009) Potential mechanisms involved in the prevention of neurodegenerative diseases by lithium. CNS Neurosci Ther15, 333–344.
12.
ChiuCT, WangZ, HunsbergerJG, ChuangDM (2013) Therapeutic potential of mood stabilizers lithium and valproic acid: Beyond bipolar disorder. Pharmacol Rev65, 105–142.
13.
VoTM, PerryP, EllerbyM, BohnertK (2015) Is lithium a neuroprotective agent?. Ann Clin Psychiatry27, 49–54.
14.
SuY, RyderJ, LiB, WuX, FoxN, SolenbergP, BruneK, PaulS, ZhouY, LiuF, NiB (2004) Lithium, a common drug for bipolar disorder treatment, regulates amyloid-beta precursor protein processing. Biochemistry43, 6899–6908.
15.
RockensteinE, TorranceM, AdameA, ManteM, Bar-onP, RoseJB, CrewsL, MasliahE (2007) Neuroprotective effects of regulators of the glycogen synthase kinase-3beta signaling pathway in a transgenic model of Alzheimer’s disease are associated with reduced amyloid precursor protein phosphorylation. J Neurosci27, 1981–1991.
16.
NakashimaH, IshiharaT, SuguimotoP, YokotaO, OshimaE, KugoA, TeradaS, HamamuraT, TrojanowskiJQ, LeeVM, KurodaS (2005) Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies. Acta Neuropathol110, 547–556.
17.
LeroyK, AndoK, HéraudC, YilmazZ, AutheletM, BoeynaemsJM, BuéeL, De DeckerR, BrionJP (2010) Lithium treatment arrests the development of neurofibrillary tangles in mutant tau transgenic mice with advanced neurofibrillary pathology. J Alzheimers Dis19, 705–719.
18.
ZhangX, HengX, LiT, LiL, YangD, ZhangX, DuY, DoodyRS, LeW (2011) Long-term treatment with lithium alleviates memory deficits and reduces amyloid-β production in an aged Alzheimer’s disease transgenic mouse model. J Alzheimers Dis24, 739–749.
19.
EngelT, Goñi-OliverP, LucasJJ, AvilaJ, HernándezF (2006) Chronic lithium administration to FTDP-17 tau and GSK-3beta overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert. J Neurochem99, 1445–1455.
20.
CaccamoA, OddoS, TranLX, LaFerlaFM (2007) Lithium reduces tau phosphorylation but not A beta or working memory deficits in a transgenic model with both plaques and tangles. Am J Pathol170, 1669–1675.
21.
SudduthTL, WilsonJG, EverhartA, ColtonCA, WilcockDM (2012) Lithium treatment of APPSwDI/NOS2-/- mice leads to reduced hyperphosphorylated tau, increased amyloid deposition and altered inflammatory phenotype. PLoS One7, e31993.
NunesMA, VielTA, BuckHS (2013) Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease. Curr Alzheimer Res10, 104–107.
25.
MatsunagaS, KishiT, AnnasP, BasunH, HampelH, IwataN (2015) Lithium as a treatment for Alzheimer’s disease: A systematic review and meta-analysis. J Alzheimers Dis48, 403–410.
26.
TsaltasE, KontisD, BoulougourisV, PapadimitriouGN (2009) Lithium and cognitive enhancement: Leave it or take it?Psychopharmacology (Berl)202, 457–476.
27.
ForlenzaOV, de PaulaVJ, Machado-VieiraR, DinizBS, GattazWF (2012) Does lithium prevent Alzheimer’s disease?Drugs Aging29, 335–342.
28.
QuirozJA, Machado-VieiraR, ZarateCAJr, ManjiHK (2010) Novel insights into lithium’s mechanism of action: Neurotrophic and neuroprotective effects. Neuropsychobiology62, 50–60.
29.
ChiuCT, ChuangDM (2010) Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders. Pharmacol Ther128, 281–304.
30.
ChiuCT, ChuangDM (2011) Neuroprotective action of lithium in disorders of the central nervous system. Zhong Nan Da Xue Xue Bao Yi Xue Ban36, 461–476.
31.
AghdamSY, BargerSW (2007) Glycogen synthase kinase-3 in neurodegeneration and neuroprotection: Lessons from lithium. Curr Alzheimer Res4, 21–31.
HoshiM, TakashimaA, NoguchiK, MurayamaM, SatoM, KondoS, SaitohY, IshiguroK, HoshinoT, ImahoriK (1996) Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain. Proc Natl Acad Sci U S A93, 2719–2723.
34.
JensenM, HoerndliFJ, BrockiePJ, WangR, JohnsonE, MaxfieldD, FrancisMM, MadsenDM, MaricqAV (2012) Wnt signaling regulates acetylcholine receptor translocation and synaptic plasticity in the adult nervous system. Cell149, 173–187.
35.
ZhaoL, ChuCB, LiJF, YangYT, NiuSQ, QinW, HaoYG, DongQ, GuanR, HuWL, WangY (2013) Glycogen synthase kinase-3 reduces acetylcholine level in striatum via disturbing cellular distribution of choline acetyltransferase in cholinergic interneurons in rats. Neuroscience255, 203–211.
36.
HawkesC, JhamandasJH, KarS (2005) Selective loss of basal forebrain cholinergic neurons by 192 IgG-saporin is associated with decreased phosphorylation of Ser glycogen synthase kinase-3beta. J Neurochem95, 263–272.
37.
WuYY, WangX, TanL, LiuD, LiuXH, WangQ, WangJZ, ZhuLQ (2013) Lithium attenuates scopolamine-induced memory deficits with inhibition of GSK-3β and preservation of postsynaptic components. J Alzheimers Dis37, 515–527.
38.
BookAA, WileyRG, SchweitzerJB (1992) Specificity of 192 IgG-saporin for NGF receptor-positive cholinergic basal forebrain neurons in the rat. Brain Res590, 350–355.
39.
HeckersS, OhtakeT, WileyRG, LappiDA, GeulaC, MesulamMM (1994) Complete and selective cholinergic denervation of rat neocortex and hippocampus but not amygdala by an immunotoxin against the p75 NGF receptor. J Neurosci14, 1271–1289.
40.
De BartoloP, GelfoF, MandolesiL, FotiF, CutuliD, PetrosiniL (2009) Effects of chronic donepezil treatment and cholinergic deafferentation on parietal pyramidal neuron morphology. J Alzheimers Dis17, 177–191.
41.
WaiteJJ, ChenAD (2001) Differential changes in rat cholinergic parameters subsequent to immunotoxic lesion of the basal forebrain nuclei. Brain Res918, 113–120.
42.
CutuliD, De BartoloP, CaporaliP, TartaglioneAM, OddiD, D’AmatoFR, NobiliA, D’AmelioM, PetrosiniL (2013) Neuroprotective effects of donepezil against cholinergic depletion. Alzheimers Res Ther5, 50.
43.
D’AmelioM, CavallucciV, MiddeiS, MarchettiC, PacioniS, FerriA, DiamantiniA, De ZioD, CarraraP, BattistiniL, MorenoS, BacciA, Ammassari-TeuleM, MarieH, CecconiF (2011) Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer’s disease. Nat Neurosci14, 69–76.
44.
D’AmelioM, ShengM, CecconiF (2012) Caspase-3 in the central nervous system: Beyond apoptosis. Trends Neurosci35, 700–709.
45.
JoJ, WhitcombDJ, OlsenKM, KerriganTL, LoSC, Bru-MercierG, DickinsonB, ScullionS, ShengM, CollingridgeG, ChoK (2011) Aβ(1-42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3β. Nat Neurosci14, 545–547.
46.
FukumotoT, MorinobuS, OkamotoY, KagayaA, YamawakiS (2001) Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain. Psychopharmacology (Berl)158, 100–106.
47.
EinatH, YuanP, GouldTD, LiJ, DuJ, ZhangL, ManjiHK, ChenG (2003) The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J Neurosci23, 7311–7316.
ShimSS, HammondsMD, MervisRF (2013) Four weeks lithium treatment alters neuronal dendrites in the rat hippocampus. Int J Neuropsychopharmacol16, 1373–1382.
50.
PaxinosG, WatsonC (1998) The rat brain in stereotaxic coordinates. 4th edition, Academic Press, San Diego, CA.
51.
CutuliD, FotiF, MandolesiL, De BartoloP, GelfoF, FedericoF, PetrosiniL (2009) Cognitive performances of cholinergically depleted rats following chronic donepezil administration. J Alzheimers Dis17, 161–176.
52.
MandolesiL, De BartoloP, FotiF, GelfoF, FedericoF, LeggioMG, PetrosiniL (2008) Environmental enrichment provides a cognitive reserve to be spent in the case of brain lesion. J Alzheimers Dis15, 11–28.
53.
De FerrariGV, ChacónMA, BarríaMI, GarridoJL, GodoyJA, OlivaresG, ReyesAE, AlvarezA, BronfmanM, InestrosaNC (2003) Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by beta-amyloid fibrils. Mol Psychiatry8, 195–208.
54.
PerioA, TerranovaJP, WormsP, BlutheRM, DantzerR, BiziereK (1989) Specific modulation of social memory in rats by cholinomimetic and nootropic drugs, by benzodiazepine inverse agonists, but not by psychostimulants. Psychopharmacology (Berl)97, 262–268.
55.
WinslowJT, CamachoF (1995) Cholinergic modulation of a decrement in social investigation following repeated contacts between mice. Psychopharmacology (Berl)121, 164–172.
56.
KoganJH, FranklandPW, SilvaAJ (2000) Long-term memory underlying hippocampus-dependent social recognition in mice. Hippocampus10, 47–56.
57.
RiedelG, KangSH, ChoiDY, PlattB (2009) Scopolamine-induced deficits in social memory in mice: Reversal by donepezil. Behav Brain Res204, 217–225.
58.
CastroAA, GhisoniK, LatiniA, QuevedoJ, TascaCI, PredigerRD (2012) Lithium and valproate prevent olfactory discrimination and short-term memory impairments in the intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rat model of Parkinson’s disease. Behav Brain Res229, 208–215.
59.
AtkinsRJ, DimouJ, ParadisoL, MorokoffAP, KayeAH, DrummondKJ, HovensCM (2012) Regulation of glycogen synthase kinase-3 beta (GSK-3β) by the Akt pathway in gliomas. J Clin Neurosci19, 1558–1563.
60.
BradleyCA, PeineauS, TaghibiglouC, NicolasCS, WhitcombDJ, BortolottoZA, KaangBK, ChoK, WangYT, CollingridgeGL (2012) A pivotal role of GSK-3 in synaptic plasticity. Front Mol Neurosci5, 13.
61.
HernándezF, Gómez de BarredaE, Fuster-MatanzoA, LucasJJ, AvilaJ (2010) GSK3: A possible link between beta amyloid peptide and tau protein. Exp Neurol223, 322–325.
62.
FreyBN, ValvassoriSS, RéusGZ, MartinsMR, PetronilhoFC, BardiniK, Dal-PizzolF, KapczinskiF, QuevedoJ (2006) Effects of lithium and valproate on amphetamine-induced oxidative stress generation in an animal model of mania. J Psychiatry Neurosci31, 326–332.
63.
GelfoF, TirassaP, De BartoloP, CaltagironeC, PetrosiniL, AngelucciF (2011) Brain and serum levels of nerve growth factor in a rat model of Alzheimer’s disease. J Alzheimers Dis25, 213–217.
64.
AngelucciF, GelfoF, De BartoloP, CaltagironeC, PetrosiniL (2011) BDNF concentrations are decreased in serum and parietal cortex in immunotoxin 192 IgG-Saporin rat model of cholinergic degeneration. Neurochem Int59, 1–4.
65.
PetrosiniL, De BartoloP, FotiF, GelfoF, CutuliD, LeggioMG, MandolesiL (2009) On whether the environmental enrichment may provide cognitive and brain reserves. Brain Res Rev61, 221–239.
66.
GelfoF, PetrosiniL, GrazianoA, De BartoloP, BurelloL, VitaleE, PolverinoA, IulianoA, SorrentinoG, MandolesiL (2013) Cortical metabolic deficits in a rat model of cholinergic basal forebrain degeneration. Neurochem Res38, 2114–2123.
67.
Cooper-KuhnCM, WinklerJ, KuhnHG (2004) Decreased neurogenesis after cholinergic forebrain lesion in the adult rat. J Neurosci Res77, 155–165.
68.
StreckEL, ScainiG, JeremiasGC, RezinGT, GonçalvesCL, FerreiraGK, RéusGZ, ResendeWR, ValvassoriSS, KapczinskiF, AndersenML, QuevedoJ (2015) Effects of mood stabilizers on brain energy metabolism in mice submitted to an animal model of mania induced by paradoxical sleep deprivation. Neurochem Res40, 1144–1152.
69.
HansonND, NemeroffCB, OwensMJ (2011) Lithium, but not fluoxetine or the corticotropin-releasing factor receptor 1 receptor antagonist R121919, increases cell proliferation in the adult dentate gyrus. J Pharmacol Exp Ther337, 180–186.
