triepens N, Scheef L, Wind A, Popp J, Spottke A,
Cooper-Mahkorn D, Suliman H, Wagner M, Schild
HH and Jessen F. Volume loss of the medial temporal
lobe structures in subjective memory impairment.
Dement. Geriatr. Cogn. Disord. (2010) 29: 75-81.
Hardy J and Selkoe DJ. The amyloid hypothesis of
alzheimer’s disease: progress and problems on the
road to therapeutics. Science (2002) 297: 353-6.
Magdesian MH, Carvalho MM, Mendes FA, Saraiva
LM, Juliano MA, Juliano L, Garcia-Abreu J and
Ferreira ST. Amyloid-beta binds to the extracellular
cysteine-rich domain of Frizzled and inhibits Wnt/
beta-catenin signaling. J. Biol. Chem. (2008) 283:
9359-68.
Dunn L, Allen GF, Mamais A, Ling H, Li A, Duberley
KE, Hargreaves IP, Pope S, Holton JL, Lees A, Heales
SJ and Bandopadhyay R. Dysregulation of glucose
metabolism is an early event in sporadic parkinson’s
disease. Neurobiol. Aging (2014) 35: 1111-5.
Ontiveros-Torres MÁ, Labra-Barrios ML, Díaz-
Cintra S, Vázquez-Aguilar A, Moreno-Campuzano
S, Flores-Rodríguez P, Luna-Herrera C, Mena R,
Perry G, Florán-Garduño B, Luna-Muñoz J and
Luna-Arias JP. Fibrillar amyloid-β accumulation
triggers an inflammatory mechanism leading to
hyperphosphorylation of the carboxyl-terminal end of
tau polypeptide in the hippocampal formation of the
3×Tg-AD transgenic mouse. J. Alzheimers Dis. (2016)
52: 243-69.
Fernandez-Perez EJ, Peters C and Aguayo LG.
Membrane damage induced by amyloid beta and a
potential link with neuroinflammation. Curr. Pharm.
Des. (2016) 22: 1295-304.
Ferré P. The biology of peroxisome proliferator-
activated receptors: relationship with lipidmetabolism
and insulin sensitivity. Diabetes (2004) 53 (Suppl 1):
S43-50.
Jiang Q, Heneka M and Landreth GE. The role of
peroxisome proliferator-activated receptor-gamma
(PPARgamma) in alzheimer’s disease: therapeutic
implications. CNS Drugs (2008) 22: 1-14.
Pedersen WA, McMillan PJ, Kulstad JJ, Leverenz JB,
Craft S and Haynatzki GR. Rosiglitazone attenuates
learning and memory deficits in Tg2576 alzheimer
mice. Exp. Neurol. (2006) 199: 265–73.
O′Reilly JA and Lynch M. Rosiglitazone improves
spatial memory and decreases insoluble Aβ(1-42) in
APP/PS1 mice. J. Neuroimmune Pharmacol. (2012)7: 140-4.
Xu S, Liu G, Bao X, Wu J, Li S, Zheng B, Anwyl
R and Wang Q. Rosiglitazone prevents amyloid-β
oligomer-induced impairment of synapse formation
and plasticity via increasing dendrite and spine
mitochondrial number. J. Alzheimers Dis. (2014) 39:
239-51.
Miller BW, Willett KC and Desilets AR. Rosiglitazone
and pioglitazone for the treatment of alzheimer′s
disease. Ann. Pharmacother. (2011) 45: 1416-24.
Heneka MT, Reyes-Irisarri E, Hüll M and Kummer
MP. Impact and therapeutic potential of PPARs in
alzheimer′s disease. Curr. Neuropharmacol. (2011)
9: 643-50.
Inestrosa N, De Ferrari GV, Garrido JL, Alvarez A,
Olivares GH, Barría MI, Bronfman M and Chacón
MA. Wnt signaling involvement in beta-amyloid-
dependent neurodegeneration. Neurochem. Int. (2002)
41: 341-4.
Inestrosa NC, Godoy JA, Quintanilla RA, Koenig
CS and Bronfman M. Peroxisome proliferator-
activated receptor gamma is expressed in hippocampal
neurons and its activation prevents beta-amyloid
neurodegeneration: role of Wnt signalling. Exp. Cell
Res. (2005) 304: 91-104.
Kaundal RK and Sharma SS. Peroxisome proliferator-
activated receptor gamma agonists as neuroprotective
agents. Drug News Perspect. (2010) 23: 241-56.
Coombs GS, Covey TM and Virshup DM. Wnt
signaling in development disease and translational
medicine. Curr. Drug Targets (2008) 9: 513–31.
Inestrosa NC and Varela-Nallar L. Wnt signaling in
thenervous system andin alzheimer’s disease. J. Mol.
Cell Biol. (2014) 6: 64-74.
Oliva CA, Vargas JY and Inestrosa NC. Wnts in
adult brain: from synaptic plasticity to cognitive
deficiencies. Front. Cell Neurosci. (2013) 7: 224.
Cerpa W, Gambrill A, Inestrosa NC and Barria A.
Regulation of NMDA-receptor synaptic transmission
by Wnt signaling. J. Neurosci. (2011) 31: 9466–71.
Zhang GL, Zhang J, Li SF, Lei L, Xie HY, Deng F,
Feng JC and Qi JS. Wnt-5a prevents Aβ-induced
deficits in long-term potentiation and spatial memory
in rats. Physiol. Behav. (2015) 149: 95-100.
Caracci MO, Ávila ME and De Ferrari GV. Synaptic
Wnt/GSK3β signaling Hub in autism. Neural Plast.
(2016) 2016: 10.
Inestrosa NC and Toledo EM. The role of Wnt signaling
in neuronal dysfunction in alzheimer’s disease. Mol.
Neurodegener. (2008) 3: 9.
Alvarez AR, Godoy JA, Mullendorff K, Olivares GH,
Bronfman M and Inestrosa NC. Wnt-3a overcomes
beta-amyloid toxicity in rat hippocampal neurons.
Exp. Cell Res. (2004) 297: 186-96.
Hayashi Y, Hirotsu T, Iwata R, Kage-Nakadai
E and Kunitomo H. A trophic role for Wnt-Ror
kinase signaling during developmental pruning in
Caenorhabditis elegans. Nat. Neurosci. (2009) 12:
981-7.
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(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
(20)
(21)
(22)
(23)
(24)
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Acknowledgement
This research was supported by Neuroscience
Research Centers of Shahid Beheshti Uinversity
of Medical Sciences and Baqiyatallah Uinversity
of Medical Sciences.
References
Bahrami F et al. / IJPR (2019), 18 (3): 1403-14181416
Iida J, Dorchak J, Lehman JR, Clancy R and Luo
C. FH535 inhibited migration and growth of breast
cancer cells. PLoS One (2012) 7: e44418.
Vilchez V, Turcios L, Marti F and Gedaly R. Targeting
Wnt/β-catenin pathway in hepatocellular carcinoma
treatment. World J. Gastroenterol. (2016) 22: 823-32 .
Brewer GJ, Torricelli JR, Evege EK and Price PJ.
Optimized survival of hippocampal neurons in B27-
supplemented Neurobasal, a new serum-free medium
combination. J. Neurosci Res. (1993) 35: 567-76.
Bahrami F and Janahmadi M. Antibiotic supplements
affect electrophysiological properties and excitability
of rat hippocampal pyramidal neurons in primary
culture. Iran. Biomed. J. (2013) 17: 101-6.
Bahrami F, Yousefpour M, Mehrani H, Golmanesh L
and Sadraee SH. A Type of cell death and the role of
acetylcholinesterase activity in neurotoxicity induced
by paraoxon in cultured rat hippocampal neurons. Acta
Biol. Hung. (2009) 60: 1-13.
Handeli S and Simon JA. A small-molecule inhibitor
of Tcf/beta-catenin signaling down-regulates
PPARgamma and PPARdelta activities. Mol. Cancer
Ther. (2008) 7: 521-9.
Kanerva L and Verkkala E. Electron microscopy and
immunohistochemistry of toxic and allergic effects of
methylmethacrylate on the skin. Arch. Toxicol. Suppl.
(1986) 9: 456-9.
Saggu SK, Chotaliya HP, Blumbergs PC and Casson
RJ. Wallerian-like axonal degeneration in the optic
nerve after excitotoxic retinal insult: an ultrastructural
study. BMC Neurosci. (2010) 11: 97.
Caricasole A, Copani A, Caruso A, Caraci F, Iacovelli
L, Sortino MA, Terstappen GC and Nicoletti F. The
Wnt pathway, cell-cycle activation and beta-amyloid:
Novel therapeutic strategies in alzheimer’s disease?
Trends Pharmacol. Sci. (2003) 24: 233-8.
De Ferrari GV, Chacón MA, Barría MI, Garrido
JL, Godoy JA, Olivares G, Reyes AE, Alvarez A,
Bronfman M and Inestrosa NC. Activation of Wnt
signaling rescues neurodegeneration and behavioral
impairments induced by beta-amyloid fibrils. Mol.
Psychiatry (2003) 8: 195-208.
Tu S, Okamoto S, Lipton SA and Xu H. Oligomeric
Aβ-induced synaptic dysfunction in alzheimer’s
disease. Mol. Neurodegener. (2014) 14: 9-48.
Carrillo-Mora P, Luna R and Colín-Barenque L.
Amyloid beta: multiple mechanisms of toxicity and
only some protective effects? Oxid. Med. Cell. Longev.
(2014) 2014: 15.
Lambert MP, Barlow AK, Chromy BA, Edwards C and
Freed R. Diffusible, nonfribrillar ligands derived from
Aβ1-42 are potent central nervous system neurotoxins
Proc. Natl. Acad. Sci. USA (1988) 95: 6448-53.
Wang HW, Pasternak JF, Kuo H, Ristic H, Lambert
MP, Chromy B, Viola KL, Klein WL, Stine WB,
Krafft GA and Trommer BL. Soluble oligomers of beta
amyloid (1–42) inhibit long-term potentiation but not
long-term depression in rat dentate gyrus. Brain Res.
(2002) 924: 133–40.
Wang Y, Zhang G, Zhou H, Barakat A and Querfurth
H. Opposite effects of low and high doses of Abeta42
on electrical network and neuronal excitability in the
rat prefrontal cortex. PLoS One (2009) 4: e8366.
Varghese K, Molnar P, Das M, Bhargava N, Lambert
S, Kindy MS and Hickman JJ. A new target for
amyloid beta toxicity validated by standard and high-
throughput electrophysiology. PLoS One (2010) 5:
e8643.
Hong-Qi Y, Zhi-Kun S and Sheng-Di C. Current
advances in the treatment of alzheimer’s disease:
focused on considerations targeting Aβ and tau. Transl.
Neurodegener. (2012) 1: 21.
Schenk D, Basi GS and Pangalos MN. Treatment
strategies targeting amyloid β-protein. Cold Spring
Harb. Perspect. Med. (2012) 2: a006387.
Karl T, Garner B and Cheng D. The therapeutic
potential of the phytocannabinoid cannabidiol for
alzheimer’s disease. Behav. Pharmacol. (2017) 28 (2
and 3-Spec Issue): 142-60.
Randy LH and Guoying B. Agonism of peroxisome
proliferator receptor-gamma may have therapeutic
potential for neuro inflammation and parkinson’s
disease. Curr. Neuropharmacol. (2007) 5: 35–46.
Schintu N, Frau L, Ibba M, Caboni P and Garau A.
PPAR-gamma-mediated neuroprotection in a chronic
mouse model of parkinson’s disease. Eur. J. Neurosci.
(2009) 29: 954–63.
Johri A, Calingasan NY, Hennessey TM, Sharma A and
Yang L. Pharmacologic activation of mitochondrial
biogenesis exerts widespread beneficial effects in a
transgenic mouse model of huntington’s disease. Hum.
Mol. Genet. (2012) 21: 1124–37.
Watson GS, Cholerton BA, Reger MA, Baker LD
and Plymate SR. Preserved cognition in patients with
early alzheimer disease and amnestic mild cognitive
impairment during treatment with rosiglitazone: a
preliminary study. Am. J. Geriatr. Psychiatry . (2005)
13: 950-8.
Jin YN, Hwang WY, Jo C and Johnson GV. Metabolic
state determines sensitivity to cellular stress in
Huntington disease: normalization by activation of
PPARgamma. PLoS One (2012) 7: e30406.
Jin J, Albertz J, Guo Z, Peng Q and Rudow G.
Neuroprotective effects of PPAR-γ agonist rosiglitazone
in N171-82 Q mouse model of huntington’s disease. J.
Neurochem. (2013) 125: 410-9.
Toledo EM and Inestrosa NC. Activation of Wnt
signaling by lithium and rosiglitazone reduced spatial
memory impairment and neurodegeneration in brains
of an APPswe/PSEN1DeltaE9 mouse model of
alzheimer’s disease. Mol. Psychiatry. (2010) 15: 272-
85.
Liu L, Zhi Q, Shen M, Gong FR, Zhou BP Lian L,
Shen B, Chen K, Duan W, Wu MY, Tao M and Li
W. FH535, a β-catenin pathway inhibitor, represses
pancreatic cancer xenograft growth and angiogenesis.
Oncotarget. (2016) 7: 47145-62.
Cheng A, Hou Y and Mattson MP. Mitochondria and
(26)
(27)
(28)
(29)
(30)
(31)
(32)
(33)
(34)
(35)
(36)
(37)
(38)
(39)
(40)
(41)
(42)
(43)
(44)
(45)
(46)
(47)
(48)
(49)
(50)
(51)
(52)
(53)
PPAR-γ involvement in Aβ neurotoxicity1417
neuroplasticity. ASN Neuro. (2010) 2: e00045.
Silva-Alvarez C, Arrazola MS, Godoy JA, Ordenes D
and Inestrosa NC. Canonical Wnt signaling protects
hippocampal neurons from Abeta oligomers: role
of non-canonical Wnt-5a/Ca(2+) in mitochondrial
dynamics. Front. Cell Neurosci. (2013) 7: 97.
Nimmrich V, Grimm C, Draguhn A, Barghorn S,
Lehmann A, Schoemaker H, Hillen H, Gross G,
Ebert U and Bruehl C. Amyloid beta oligomers (A
beta(1-42) globulomer) suppress spontaneous synaptic
activity by inhibition of P/Q-type calcium currents. J.
Neurosci. (2008) 28: 788-97.
Yun SH, Gamkrelidze G, Stine WB, Sullivan PM
and Pasternak JF. Amyloid-beta1-42 reduces neuronal
excitability in mouse dentate gyrus. Neurosci. Lett.
(2006) 403: 162-5.
Kaczorowski CC, Sametsky E, Shah S, Vassar R
and Disterhoft JF. Mechanisms underlying basal and
learning-related intrinsic excitability in a mouse model
of alzheimer’s disease. Neurobiol. Aging (2011) 32:
1452-65.
Chen QS, Kagan BL, Hirakura Y and Xie CW.
Impairment of hippocampal long-term potentiation
by alzheimer amyloid beta-peptides. J. Neurosci. Res.
(2000) 60: 65–72.
Puzzo D, Privitera L, Leznik E, Fa` M, Staniszewski
A, Palmeri A and Arancio O. Picomolar amyloid-beta
positively modulates synaptic plasticity and memory
in hippocampus. J. Neurosci. (2008) 28: 14537–45.
Jin M, Shepardson N, Yang T, Chen G, Walsh D
and Selkoe DJ. Soluble amyloid beta-protein dimers
isolated from alzheimer cortex directly induce Tau
hyperphosphorylation and neuritic degeneration. Proc.
Natl. Acad. Sci. USA (2011) 108: 5819–24.
Arispe N, Rojas E and Pollard HB. Alzheimer disease
amyloid beta protein forms calcium channels in
bilayer membranes: blockade by tromethamine and
aluminium. Proc. Natl. Acad. Sci. USA (1993) 90:
567-71.
Kawahara M and Kuroda Y. Molecular mechanism
of neurodegeneration induced by alzheimer’s beta-
amyloid protein: channel formation and disruption
of calcium homeostasis. Brain Res. Bull. (2000) 53:
389-97.
Heneka MT, Sastre M, Dumitrescu-Ozimek L,
Hanke A and Dewachter I. Acute treatment with the
PPARgamma agonist pioglitazone and ibuprofen
reduces glial inflammation and Abeta1-42 levels in
APPV717I transgenic mice. Brain (2005) 28 (Pt 6):
1442-53.
Feinstein DL, Galea E, Gavrilyuk V, Brosnan CF
and Whitacre CC. Peroxisome proliferator-activated
receptor-gamma agonists prevent experimental
autoimmune encephalomyelitis. Ann. Neurol. (2001)
51: 694-702.
Patlak J. Molecular kinetics of voltage-dependent Na+
channels. Physiol. Rev. (1991) 71: 1047–80.
Vervaeke K, Hu H, Graham LJ and Storm JF.
Contrasting effects of the persistent Na+ current on
(54)
(55)
(56)
(57)
(58)
(59)
(60)
(61)
(62)
(63)
(64)
(65)
(66)
neuronal excitability and spike timing. Neuron (2006)
49: 257–70.
Brown JT, Chin J, Leiser SC, Pangalos MN and
Randall AD. Altered intrinsic neuronal excitability and
reduced Na+ currents in a mouse model of alzheimer’s
disease. Neurobiol. Aging (2011) 32: 2109e1-14.
Prakash A and Kumar A. Role of nuclear receptor
on regulation of BDNF and neuroinflammation
in hippocampus of β-amyloid animal model of
alzheimer’s disease. Neurotox. Res. (2014) 25: 335-47.
Chen TS, Lai MC, Hung TY, Lin KM, Huang CW and
Wu SN. Pioglitazone, a PPAR-γ Activator, Stimulates
BKCa but Suppresses IK M in Hippocampal Neurons.
Front. Pharmacol. (2018) 9: 977.
Tubert C, Taravini IRE, Flores-Barrera E, Sánchez
GM, Prost MA, Avale ME, Tseng KY, Rela L and
Murer MG. Decrease of a current mediated by kv1.3
channels causes striatal cholinergic interneuron
hyperexcitability in experimental parkinsonism. Cell
Rep. (2016) 16: 2749-62.
Johnston J, Forsythe ID and Kopp-Scheinpflug C.
Going native: voltage-gated potassium channels
controlling neuronal excitability. J. Physiol. (2010)
588 (Pt 17): 3187-200.
Golowasch J, Thomas G, Taylor AL, Patel A, Pineda
A, Khalil C and Nadim F. Membrane capacitance
measurements revisited: dependence of capacitance
value on measurement method in nonisopotential
neurons. J. Neurophysiol. (2009) 102: 2161-75.
Gilman JP, Medalla M and Luebke JI. Area-specific
features of pyramidal neurons-a comparative study in
mouse and rhesus monkey. Cereb. Cortex (2017) 27:
2078-94.
Matsumura R, Yamamoto H, Hayakawa T,
Katsurabayashi S, Niwano M and Hirano-Iwata A.
Dependence and homeostasis of membrane impedance
on cell morphology in cultured hippocampal neurons.
Sci. Rep. (2018) 8: 9905.
Brager DH, Akhavan AR and Johnston D. Impaired
dendritic expression and plasticity of h-channels in the
fmr1(-/y) mouse model of fragile X syndrome. Cell
Rep. (2012) 1: 225-33.
Eslamizade MJ, Saffarzadeh F, Mousavi SM, Meftahi
GH, Hosseinmardi N, Mehdizadeh M and Janahmadi
M. Alterations in CA1 pyramidal neuronal intrinsic
excitability mediated by Ih channel currents in a rat
model of amyloid beta pathology. Neurosci. (2015)
305: 279-92.
Lesage F. Pharmacology of neuronal background
potassium channels. Neuropharmacol. (2003) 44: 1-7.
Cameron WE, Núñez-Abades PA and Kerman IA and
Hodgson TM. Role of potassium conductances in
determining input resistance of developing brain stem
motoneurons. J. Neurophysiol. (2000) 84: 2330-9.
Pasantes-Morales H and Tuz K. Volume changes
in neurons: hyperexcitability and neuronal death.
Contrib. Nephrol. (2006) 152: 221-40.
Yang JW, Ru J, Ma W, Gao Y, Liang Z, Liu J, Guo
JH and Li LY. BDNF promotes the growth of human
(67)
(68)
(69)
(70)
(71)
(72)
(73)
(74)
(75)
(76)
(77)
(78)
(79)
(80)
Bahrami F et al. / IJPR (2019), 18 (3): 1403-14181418
neurons through crosstalk with the Wnt/β-catenin
signaling pathway via GSK-3β. Neuropeptides (2015)
54: 35-46.
Lange C, Mix E, Rateitschak K and Rolfs A. Wnt(81)
signal pathways and neural stem cell differentiation.
Neurodegener. Dis. (2006) 3: 76-86.