Cognitive deficit is mainly clinical characteristic of Alzheimer’s disease (AD). Recent reports showed adiponectin and its analogues could reverse cognitive impairments, lower amyloid-β protein (Aβ) deposition, and exert anti-inflammatory effects in different APP/PS1 AD model mice mainly exhibiting amyloid plaque pathology. However, the potential in vivo electrophysiological mechanism of adiponectin protecting against cognitive deficits in AD and the neuroprotective effects of adiponectin on 3xTg-AD mice including both plaque and tangle pathology are still unclear.
Objective:
To observe the effects of adiponectin treatment on cognitive deficits in 3xTg-AD mice, investigate its potential in vivo electrophysiological mechanism, and testify its anti-inflammatory effects.
Methods:
Barnes maze test, Morris water maze test, and fear conditioning test were used to evaluate the memory-ameliorating effects of adiponectin on 3xTg-AD mice. In vivo hippocampal electrophysiological recording was used to observe the change of basic synaptic transmission, long-term potentiation, and long-term depression. Immunohistochemistry staining and western blot were used to observe the activation of microglia and astroglia, and the expression levels of proinflammatory factors and anti-inflammtory factor IL-10.
Results:
Adiponectin treatment could alleviate spatial memory and conditioned fear memory deficits observed in 3xTg-AD mice, improve in vivo LTP depression and LTD facilitation, inhibit overactivation of microglia and astroglia, decrease the expression of proinflammatory factors NF- κB and IL-1β, and increase the expression level of IL-10 in the hippocampus of 3xTg-AD mice.
Conclusion:
Adiponectin could ameliorate cognitive deficits in 3xTg-AD mice through improving in vivo synaptic plasticity impairments and alleviating neuroinflammation in the hippocampus of 3xTg-AD mice.
Forny-GermanoL, De FeliceFG, VieiraM (2018) The role of leptin and adiponectin in obesity-associated cognitive decline and Alzheimer’s disease. Front Neurosci12, 1027.
10.
NgRC-L, ChengO-Y, JianM, KwanJS-C, HoPW-L, ChengKK-Y, YeungPKK, ZhouLL, HooRL-C, ChungSK, XuA, LamKS-L, ChanKH (2016) Chronic adiponectin deficiency leads to Alzheimer’s disease-like cognitive impairments and pathologies through AMPK inactivation and cerebral insulin resistance in aged mice. Mol Neurodegener11, 71.
11.
NgRC-L, JianM, MaOK-F, BuntingM, KwanJS-C, ZhouG-J, SenthilkumarK, IyaswamyA, ChanP-K, LiM, LeungKM-Y, Kumar DurairajanS-S, LamKS-L, ChuL-W, FestensteinR, ChungSK, ChanK-H (2020) Chronic oral administration of adipoRon reverses cognitive impairments and ameliorates neuropathology in an Alzheimer’s disease mouse model. Mol Psychiatry, doi: 10.1038/s41380-020-0701-0.
12.
WangM, JoJ, SongJ (2019) Adiponectin improves long-term potentiation in the 5XFAD mouse brain. Sci Rep9, 8918.
13.
LiuB, LiuJ, WangJG, LiuCL, YanHJ (2020) AdipoRon improves cognitive dysfunction of Alzheimer’s disease and rescues impaired neural stem cell proliferation through AdipoR1/AMPK pathway. Exp Neurol327, 113249.
14.
OakleyH, ColeSL, LoganS, MausE, ShaoP, CraftJ, Guillozet-BongaartsA, OhnoM, DisterhoftJ, Van EldikL, BerryR, VassarR (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: Potential factors in amyloid plaque formation. J Neurosci26, 10129–10140.
15.
BlissTV, CollingridgeGL (1993) A synaptic model of memory: Long-term potentiation in the hippocampus. Nature361, 31–39.
LeeH, TuTH, ParkBS, YangS, KimJG (2019) Adiponectin reverses the hypothalamic microglial inflammation during short-term exposure to fat-rich diet. Int J Mol Sci20, 5738.
22.
SongJ, ChoiS-M, KimBC (2017) Adiponectin regulates the polarization and function of microglia via PPAR-γ signaling under amyloid β toxicity. Front Cell Neurosci11, 64.
OddoS, CaccamoA, ShepherdJD, MurphyMP, GoldeTE, KayedR, MetherateR, MattsonMP, AkbariY, LaFerlaFM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: Intracellular Abeta and synaptic dysfunction. Neuron39, 409–421.
25.
LiuJ, GuoM, ZhangD, ChengS-Y, LiuM, DingJ, SchererPE, LiuF, LuX-Y (2012) Adiponectin is critical in determining susceptibility to depressive behaviors and has antidepressant-like activity. Proc Natl Acad Sci U S A109, 12248–12253.
26.
IwamaS, SugimuraY, MuraseT, HiroiM, GotoM, HayashiM, ArimaH, OisoY (2009) Central adiponectin functions to inhibit arginine vasopressin release in conscious rats. J Neuroendocrinol21, 753–759.
27.
HayashiT, ShimonakaS, ElahiM, MatsumotoSE, IshiguroK, TakanashiM, HattoriN, MotoiY (2021) Learning deficits accompanied by microglial proliferation after the long-term post-injection of Alzheimer’s disease brain extract in mouse brains. J Alzheimers Dis79, 1701–1711.
StoverKR, CampbellMA, Van WinssenCM, BrownRE (2015) Early detection of cognitive deficits in the 3xTg-AD mouse model of Alzheimer’s disease. Behav Brain Res289, 29–38.
30.
Russo-SavageL, RaoVKS, EipperBA, MainsRE (2020) Role of Kalirin and mouse strain in retention of spatial memory training in an Alzheimer’s disease model mouse line. Neurobiol Aging95, 69–80.
31.
StojakovicA, ChangSY, NesbittJ, PichurinNP, OstrootMA, AikawaT, KanekiyoT, TrushinaE (2021) Partial inhibition of mitochondrial complex I reduces tau pathology and improves energy homeostasis and synaptic function in 3xTg-AD mice. J Alzheimers Dis79, 335–353.
32.
IzquierdoI, FuriniCR, MyskiwJC (2016) Fear memory. Physiol Rev96, 695–750.
33.
DieringGH, HuganirRL (2018) The AMPA receptor code of synaptic plasticity. Neuron100, 314–329.
34.
YangJ-T, WangZ-J, CaiH-Y, YuanL, HuM-M, WuM-N, QiJ-S (2018) Sex differences in neuropathology and cognitive behavior in APP/PS1/tau triple-transgenic mouse model of Alzheimer’s disease. Neurosci Bull34, 736–746.
35.
LiS, JinM, LiuL, DangY, OstaszewskiBL, SelkoeDJ (2018) Decoding the synaptic dysfunction of bioactive human AD brain soluble Aβ to inspire novel therapeutic avenues for Alzheimer’s disease. Acta Neuropathol Commun6, 121.
36.
BakotaL, BrandtR (2016) Tau biology and tau-directed therapies for Alzheimer’s disease. Drugs76, 301–313.
37.
CalsolaroV, EdisonP (2016) Neuroinflammation in Alzheimer’s disease: Current evidence and future directions. Alzheimers Dement12, 719–732.
38.
ChiquitaS, RibeiroM, CastelhanoJ, OliveiraF, SerenoJ, BatistaM, AbrunhosaA, Rodrigues-NevesAC, CarechoR, BaptistaF, GomesC, MoreiraPI, AmbrosioAF, Castelo-BrancoM (2019) A longitudinal multimodal in vivo molecular imaging study of the 3xTg-AD mouse model shows progressive early hippocampal and taurine loss. Hum Mol Genet28, 2174–2188.
39.
PairojanaT, PhasukS, SureshP, HuangSP, PakaprotN, ChompoopongS, HsiehTC, LiuIY (2021) Age and gender differences for the behavioral phenotypes of 3xTg alzheimer’s disease mice. Brain Res1762, 147437.
40.
VorheesCV, WilliamsMT (2006) Morris water maze: Procedures for assessing spatial and related forms of learning and memory. Nat Protoc1, 848–858.
41.
YangC, BaoX, ZhangL, LiY, LiL, ZhangL (2020) Cornel iridoid glycoside ameliorates cognitive deficits in APP/PS1/tau triple transgenic mice by attenuating amyloid-beta, tau hyperphosphorylation and neurotrophic dysfunction. Ann Transl Med8, 328.
42.
LiT, JiaoJJ, HolscherC, WuMN, ZhangJ, TongJQ, DongXF, QuXS, CaoY, CaiHY, SuQ, QiJS (2018) A novel GLP-1/GIP/Gcg triagonist reduces cognitive deficits and pathology in the 3xTg mouse model of Alzheimer’s disease. Hippocampus28, 358–372.
43.
ChenS, SunJ, ZhaoG, GuoA, ChenY, FuR, DengY (2017) Liraglutide improves water maze learning and memory performance while reduces hyperphosphorylation of tau and neurofilaments in APP/PS1/tau triple transgenic mice. Neurochem Res42, 2326–2335.
44.
XuZ-P, GanG-S, LiuY-M, XiaoJ-S, LiuH-X, MeiB, ZhangJ-J (2018) Adiponectin attenuates streptozotocin-induced tau hyperphosphorylation and cognitive deficits by rescuing PI3K/Akt/GSK-3β pathway. Neurochem Res43, 316–323.
45.
ShahSA, YoonGH, ChungSS, AbidMN, KimTH, LeeHY, KimMO (2017) Novel osmotin inhibits SREBP2 via the AdipoR1/AMPK/SIRT1 pathway to improve Alzheimer’s disease neuropathological deficits. Mol Psychiatry22, 407–416.
46.
TakeuchiT, DuszkiewiczAJ, MorrisRG (2014) The synaptic plasticity and memory hypothesis: Encoding, storage and persistence. Philos Trans R Soc Lond B Biol Sci369, 20130288.
47.
AloniE, Oni-BitonE, TsooryM, MoallemDH, SegalM (2019) Synaptopodin deficiency ameliorates symptoms in the 3xTg mouse model of Alzheimer’s disease. J Neurosci39, 3983–3992.
ChungWS, WelshCA, BarresBA, StevensB (2015) Do glia drive synaptic and cognitive impairment in disease?Nat Neurosci18, 1539–1545.
52.
MedeirosR, LaFerlaFM (2013) Astrocytes: Conductors of the Alzheimer disease neuroinflammatory symphony. Exp Neurol239, 133–138.
53.
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.
54.
GuoH, ChengY, WangC, WuJ, ZouZ, NiuB, YuH, WangH, XuJ (2017) FFPM, a PDE4 inhibitor, reverses learning and memory deficits in APP/PS1 transgenic mice via cAMP/PKA/CREB signaling and anti-inflammatory effects. Neuropharmacology116, 260–269.
Van der JeugdA, Parra-DamasA, Baeta-CorralR, Soto-FaguásCM, AhmedT, LaFerlaFM, Giménez-LlortL, D’HoogeR, SauraCA (2018) Reversal of memory and neuropsychiatric symptoms and reduced tau pathology by selenium in 3xTg-AD mice. Sci Rep8, 6431.
59.
RosenbergRN, FuM, Lambracht-WashingtonD (2018) Active full-length DNA Aβ immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology. Alzheimers Res Ther10, 115.
60.
BelfioreR, RodinA, FerreiraE, VelazquezR, BrancaC, CaccamoA, OddoS (2019) Temporal and regional progression of Alzheimer’s disease-like pathology in 3xTg-AD mice. Aging Cell18, e12873.
61.
Frontiñán-RubioJ, Sancho-BielsaFJ, PeinadoJR, LaFerlaFM, Giménez-LlortL, Durán-PradoM, AlcainFJ (2018) Sex-dependent co-occurrence of hypoxia andβ-amyloid plaques in hippocampus and entorhinal cortex isreversed by long-term treatment with ubiquinol and ascorbic acid inthe 3×Tg-AD mouse model of Alzheimer’s disease. MolCell Neurosci92, 67–81.
62.
BillingsLM, OddoS, GreenKN, McGaughJL, LaFerlaFM (2005) Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron45, 675–688.
63.
GaoY, TanL, YuJT, TanL (2018) Tau in Alzheimer’s disease: Mechanisms and therapeutic strategies. Curr Alzheimer Res15, 283–300.
