Blockade of adenosine A2A receptors recovers early deficits of memory and plasticity in the triple transgenic mouse model of Alzheimer's disease

doi:10.1016/j.nbd.2018.05.024

Neurobiology of Disease

Volume 117, September 2018, Pages 72-81

https://doi.org/10.1016/j.nbd.2018.05.024 Get rights and content

Highlights

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3xTg-AD mice at 5 months display memory and synaptic deficits with A_2AR up-regulation.
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A 3-weeks treatment with an A_2AR antagonist recovers memory and synaptic deficits.
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Normalization of hippocampal A_2AR density accompanies the recovery of early AD deficits.

Abstract

Alzheimer's disease (AD) begins with a deficit of synaptic function and adenosine A_2A receptors (A_2AR) are mostly located in synapses controlling synaptic plasticity. The over-activation of adenosine A_2A receptors (A_2AR) causes memory deficits and the blockade of A_2AR prevents memory damage in AD models. We now enquired if this prophylactic role of A_2AR might be extended to a therapeutic potential. We used the triple transgenic model of AD (3xTg-AD) and defined that the onset of memory dysfunction occurred at 4 months of age in the absence of locomotor or emotional alterations. At the onset of memory deficits, 3xTg mice displayed a decreased density of markers of excitatory synapses (10.6 ± 3.8% decrease of vGluT1) without neuronal or glial overt damage and an increase of synaptic A_2AR in the hippocampus (130 ± 22%). After the onset of memory deficits in 3xTg-AD mice, a three weeks treatment with the selective A_2AR antagonist normalized the up-regulation of hippocampal A_2AR and restored hippocampal-dependent reference memory, as well as the decrease of hippocampal synaptic plasticity (60.0 ± 3.7% decrease of long-term potentiation amplitude) and the decrease of global (syntaxin-I) and glutamatergic synaptic markers (vGluT1). These findings show a therapeutic-like ability of A_2AR antagonists to recover synaptic and memory dysfunction in early AD.

Introduction

Alzheimer's disease (AD) is an evolving neurodegenerative disorder, which begins with a selective deterioration of cognitive capabilities (Mayeux, 2010). The etiology of AD is currently unknown and there are no available therapeutic options with sufficient efficacy to revert let alone attenuate the evolution of AD (Selkoe, 2013). The onset of memory deficits in AD is not due to neuronal loss, but is instead tightly associated with the loss of functional synapses (reviewed in Selkoe, 2002) in particular in the hippocampus (Scheff et al., 2006) with glutamatergic synapses displaying a particular susceptibility (Canas et al., 2014; Hardy et al., 1987; Kirvell et al., 2006). This has prompted the suggestion that synaptic modulators might be promising targets to interfere with memory dysfunction in early AD (Coleman et al., 2004).

Accordingly, several groups have shown that the manipulation of the synaptic modulation system operated by adenosine A_2A receptors (A_2AR) affords a robust neuroprotection (reviewed in Cunha, 2016) and prevents memory dysfunction in different animal models of AD (Canas et al., 2009a; Dall'Igna et al., 2007; Laurent et al., 2016; Orr et al., 2018; Viana da Silva et al., 2016). These A_2AR are most abundantly located in synapses in the hippocampus (Rebola et al., 2005a, Rebola et al., 2005b, Rebola et al., 2005c) and selectively control synaptic plasticity processes (Costenla et al., 2011; Rebola et al., 2008). A_2AR are up-regulated upon aging (Canas et al., 2009b; Costenla et al., 2011; Cunha et al., 1995) and upon AD-like conditions in patients (Albasanz et al., 2008) and animal models (Espinosa et al., 2013; Viana da Silva et al., 2016), mostly in glutamatergic synapses (Kaster et al., 2015; Machado et al., 2017), to critically disrupt synaptic plasticity (Viana da Silva et al., 2016). The key role of A_2AR in proper memory performance is further heralded by the observation that the abnormal activation of hippocampal A_2AR is sufficient to trigger memory dysfunction (Li et al., 2015; Pagnussat et al., 2015). This evidence is in notable agreement with the association of the intake of coffee and caffeine (an adenosine receptor antagonist) with a lower incidence of dementia (e.g. Eskelinen et al., 2009; Gelber et al., 2011; Liu et al., 2016; Santos et al., 2010; Sugiyama et al., 2016). Furthermore, it was recently identified an association between A_2AR (ADORA2A) and hippocampal volume in mild cognitive impairment and AD in a gene-based association analysis in cognitively normal and impaired participants (Horgusluoglu-Moloch et al., 2017).

However, it is still not established if the pharmacological blockade of A_2AR can actually recover memory deficits at the onset of AD. Thus, we now used a genetic mouse model of AD, with three cumulative mutations in TauP301L, APP_Swe and γ-secretase (PS1M146V) – the triple transgenic model of AD (3xTg-AD) that mimics several features of AD (Oddo et al., 2003), to test if the pharmacological blockade of A_2AR is sufficient to recover the early memory deficits.

Section snippets

Animals

We used male mice from the triple transgenic model of Alzheimer's disease (3xTgAD; Oddo et al., 2003) and from its background strain, wild-type (WT) non-transgenic mice (C57BL6/129sv) obtained from our colony (Guedes et al., 2014; Lopes et al., 2009) that was derived from LaFerla's group at the Institute for Brain Aging. Thus, 3xTg-AD and control mice were not littermates but rather bred in parallel. Mice were maintained in groups of 3 per cage with some environmental enrichment (tubes and

A_2AR blockade recovers memory dysfunction

At circa 140 days of age, there was no difference in the spontaneous locomotion of male 3xTg-AD and WT mice, as assessed by the number of crossings in the open field arena (F_1,32 = 0.5208; P = 0.4757) and there was no effect of the treatment with SCH58261 (F_1,32 = 0.1547; P = 0.6967) or interaction between drug and genotype (F_1,32 = 0.0306; P = 0.8622) (Fig. 1A). Rearing activity (vertical exploration), which is informative of sensorimotor coordination, was also unaffected by either genotype (F

Discussion

The present study shows that a daily treatment during three weeks with a selective A_2AR antagonist (SCH58261, see Lopes et al., 2004) was sufficient to recover memory deficits, which were the first evident behavioral modifications found at four and a half months of age in a model of AD, the 3xTg-AD mice, harboring APPswe, PS1M146V and tauP301L mutations (Oddo et al., 2003); these memory deficits of 3xTg-AD mice were accompanied by a decreased density of synaptic markers and by deficits of

Conclusion

In summary, the present study documents a therapeutic-like ability of an A_2AR antagonist to simultaneously recover memory dysfunction, the loss of synaptic proteins and the dysfunction of synaptic plasticity in an animal model of early AD. Strikingly, the treatment with an A_2AR antagonist also normalized the up-regulated A_2AR in hippocampal synapses, which further support a key role of A_2AR over-functioning as a causative factor in the onset of AD.

Acknowledgments

This work was supported by Maratona da Saúde, GAI-FMUC and Banco Santander-Totta, Santa Casa da Misericórdia, Centro 2020 (projects CENTRO-01-0145-FEDER-000008:BrainHealth 2020 and CENTRO-01-0246-FEDER-000010), and through FCT (projects PTDC/NEU-NMC/4154/2014 and POCI-01-0145-FEDER-031274). AVP received a grant (PD/BD/106041/2015) from PhDOC PhD Programme.

Declaration of interests

R.A. Cunha is a scientific consultant of the Institute for Scientific Information on Coffee (ISIC). All other authors have no interests to declare.

References (87)

W.W. Anderson et al.
The LTP Program: a data acquisition program for on-line analysis of long-term potentiation and other synaptic events
J. Neurosci. Methods
(2001)
G.W. Arendash et al.
Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production
Neuroscience
(2006)
F.L. Assini et al.
Object location memory in mice: pharmacological validation and further evidence of hippocampal CA1 participation
Behav. Brain Res.
(2009)
P.M. Canas et al.
Modification upon aging of the density of presynaptic modulation systems in the hippocampus
Neurobiol. Aging
(2009)
P.M. Canas et al.
Predominant loss of glutamatergic terminal markers in a β-amyloid peptide model of Alzheimer's disease
Neuropharmacology
(2014)
T. Cañete et al.
Cognitive and emotional alterations in young Alzheimer's disease (3xTgAD) mice: effects of neonatal handling stimulation and sexual dimorphism
Behav. Brain Res.
(2015)
Y.F. Chu et al.
Crude caffeine reduces memory impairment and amyloid β(1–42) levels in an Alzheimer's mouse model
Food Chem.
(2012)
J.K. Clark et al.
Alterations in synaptic plasticity coincide with deficits in spatial working memory in presymptomatic 3xTg-AD mice
Neurobiol. Learn. Mem.
(2015)
G.M. Cunha et al.
Increased density and synapto-protective effect of adenosine A_2A receptors upon sub-chronic restraint stress
Neuroscience
(2006)
O.P. Dall'Igna et al.
Caffeine and adenosine A_2a receptor antagonists prevent β-amyloid (25–35)-induced cognitive deficits in mice
Exp. Neurol.
(2007)

F. Dellu et al.

Genetic differences in response to novelty and spatial memory using a two-trial recognition task in mice

Neurobiol. Learn. Mem.

(2000)

B.B. Fredholm et al.

Adenosine and brain function

Int. Rev. Neurobiol.

(2005)

L. Giménez-Llort et al.

Modeling behavioral and neuronal symptoms of Alzheimer's disease in mice: a role for intraneuronal amyloid

Neurosci. Biobehav. Rev.

(2007)

S. Gyoneva et al.

Altered motility of plaque-associated microglia in a model of Alzheimer's disease

Neuroscience

(2016)

J. Hardy et al.

Region-specific loss of glutamate innervation in Alzheimer's disease

Neurosci. Lett.

(1987)

E. Horgusluoglu-Moloch et al.

Targeted neurogenesis pathway-based gene analysis identifies ADORA2A associated with hippocampal volume in mild cognitive impairment and Alzheimer's disease

Neurobiol. Aging

(2017)

M.C. Janelsins et al.

Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice

Am. J. Pathol.

(2008)

C. Laurent et al.

Beneficial effects of caffeine in a transgenic model of Alzheimer's disease-like tau pathology

Neurobiol. Aging

(2014)

Q.P. Liu et al.

Habitual coffee consumption and risk of cognitive decline/dementia: a systematic review and meta-analysis of prospective cohort studies

Nutrition

(2016)

S. Oddo et al.

Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction

Neuron

(2003)

A.G. Orr et al.

Istradefylline reduces memory deficits in aging mice with amyloid pathology

Neurobiol. Dis.

(2018)

P. Pandolfo et al.

Caffeine regulates frontocorticostriatal dopamine transporter density and improves attention and cognitive deficits in an animal model of attention deficit hyperactivity disorder

Eur. Neuropsychopharmacol.

(2013)

L. Prut et al.

The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review

Eur. J. Pharmacol.

(2003)

N. Rebola et al.

Different synaptic and subsynaptic localization of adenosine A_2A receptors in the hippocampus and striatum of the rat

Neuroscience

(2005)

N. Rebola et al.

Adenosine A₁ and A_2A receptors are co-expressed in pyramidal neurons and co-localized in glutamatergic nerve terminals of the rat hippocampus

Neuroscience

(2005)

N. Rebola et al.

Adenosine A_2A receptors are essential for long-term potentiation of NMDA-EPSCs at hippocampal mossy fiber synapses

Neuron

(2008)

S.W. Scheff et al.

Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment

Neurobiol. Aging

(2006)

M.C. de Wilde et al.

Meta-analysis of synaptic pathology in Alzheimer's disease reveals selective molecular vesicular machinery vulnerability

Alzheimers Dement.

(2016)

J.L. Albasanz et al.

Up-regulation of adenosine receptors in the frontal cortex in Alzheimer's disease

Brain Pathol.

(2008)

G.W. Arendash et al.

Caffeine reverses cognitive impairment and decreases brain amyloid-beta levels in aged Alzheimer's disease mice

J. Alzheimers Dis.

(2009)

A. Auffret et al.

Age-dependent impairment of spine morphology and synaptic plasticity in hippocampal CA1 neurons of a presenilin 1 transgenic mouse model of Alzheimer's disease

J. Neurosci.

(2009)

V.L. Batalha et al.

Adenosine A_2A receptor blockade reverts hippocampal stress-induced deficits and restores corticosterone circadian oscillation

Mol. Psychiatry

(2013)

V.L. Batalha et al.

The caffeine-binding adenosine A_2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function

Sci. Rep.

(2016)

T. Bittner et al.

Multiple events lead to dendritic spine loss in triple transgenic Alzheimer's disease mice

PLoS One

(2010)

M. Brendel et al.

Glial activation and glucose metabolism in a transgenic amyloid mouse model: a triple-tracer PET study

J. Nucl. Med.

(2016)

P.M. Canas et al.

Adenosine A_2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by β-amyloid peptides via p38 mitogen-activated protein kinase pathway

J. Neurosci.

(2009)

C. Cao et al.

High blood caffeine levels in MCI linked to lack of progression to dementia

J. Alzheimers Dis.

(2012)

G.P. Cognato et al.

Caffeine and an adenosine A_2A receptor antagonist prevent memory impairment and synaptotoxicity in adult rats triggered by a convulsive episode in early life

J. Neurochem.

(2010)

P. Coleman et al.

A focus on the synapse for neuroprotection in Alzheimer disease and other dementias

Neurology

(2004)

A.R. Costenla et al.

Enhanced role of adenosine A_2A receptors in the modulation of LTP in the rat hippocampus upon ageing

Eur. J. Neurosci.

(2011)

R.A. Cunha

How does adenosine control neuronal dysfunction and neurodegeneration?

J. Neurochem.

(2016)

R.A. Cunha et al.

Chronic caffeine consumption prevents memory disturbance in different animal models of memory decline

J. Alzheimers Dis.

(2010)

R.A. Cunha et al.

Modification of A₁ and A_2a adenosine receptor binding in aged striatum, hippocampus and cortex of the rat

Neuroreport

(1995)

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¹: Equal experimental contribution.

²: Equal contribution in the coordination of this study.

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Blockade of adenosine A2A receptors recovers early deficits of memory and plasticity in the triple transgenic mouse model of Alzheimer's disease

Highlights

Abstract

Introduction

Section snippets

Animals

A2AR blockade recovers memory dysfunction

Discussion

Conclusion

Acknowledgments

Declaration of interests

J. Neurosci. Methods

Neuroscience

Behav. Brain Res.

Neurobiol. Aging

Neuropharmacology

Behav. Brain Res.

Food Chem.

Neurobiol. Learn. Mem.

Neuroscience

Exp. Neurol.

Neurobiol. Learn. Mem.

Int. Rev. Neurobiol.

Neurosci. Biobehav. Rev.

Neuroscience

Neurosci. Lett.

Neurobiol. Aging

Am. J. Pathol.

Neurobiol. Aging

Nutrition

Neuron

Neurobiol. Dis.

Eur. Neuropsychopharmacol.

Eur. J. Pharmacol.

Neuroscience

Neuroscience

Neuron

Neurobiol. Aging

Alzheimers Dement.

Up-regulation of adenosine receptors in the frontal cortex in Alzheimer's disease

Brain Pathol.

Caffeine reverses cognitive impairment and decreases brain amyloid-beta levels in aged Alzheimer's disease mice

J. Alzheimers Dis.

Age-dependent impairment of spine morphology and synaptic plasticity in hippocampal CA1 neurons of a presenilin 1 transgenic mouse model of Alzheimer's disease

J. Neurosci.

Adenosine A2A receptor blockade reverts hippocampal stress-induced deficits and restores corticosterone circadian oscillation

Mol. Psychiatry

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Sci. Rep.

Multiple events lead to dendritic spine loss in triple transgenic Alzheimer's disease mice

PLoS One

Glial activation and glucose metabolism in a transgenic amyloid mouse model: a triple-tracer PET study

J. Nucl. Med.

Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by β-amyloid peptides via p38 mitogen-activated protein kinase pathway

J. Neurosci.

High blood caffeine levels in MCI linked to lack of progression to dementia

J. Alzheimers Dis.

Caffeine and an adenosine A2A receptor antagonist prevent memory impairment and synaptotoxicity in adult rats triggered by a convulsive episode in early life

J. Neurochem.

A focus on the synapse for neuroprotection in Alzheimer disease and other dementias

Neurology

Enhanced role of adenosine A2A receptors in the modulation of LTP in the rat hippocampus upon ageing

Eur. J. Neurosci.

How does adenosine control neuronal dysfunction and neurodegeneration?

J. Neurochem.

Chronic caffeine consumption prevents memory disturbance in different animal models of memory decline

J. Alzheimers Dis.

Modification of A1 and A2a adenosine receptor binding in aged striatum, hippocampus and cortex of the rat

Neuroreport

Blockade of adenosine A_2A receptors recovers early deficits of memory and plasticity in the triple transgenic mouse model of Alzheimer's disease

A_2AR blockade recovers memory dysfunction

Adenosine A_2A receptor blockade reverts hippocampal stress-induced deficits and restores corticosterone circadian oscillation

The caffeine-binding adenosine A_2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function

Adenosine A_2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by β-amyloid peptides via p38 mitogen-activated protein kinase pathway

Caffeine and an adenosine A_2A receptor antagonist prevent memory impairment and synaptotoxicity in adult rats triggered by a convulsive episode in early life

Enhanced role of adenosine A_2A receptors in the modulation of LTP in the rat hippocampus upon ageing

Modification of A₁ and A_2a adenosine receptor binding in aged striatum, hippocampus and cortex of the rat