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3,4-Dihydroxyphenylethanol Assuages Cognitive Impulsivity in Alzheimer’s Disease by Attuning HPA-axis via Differential Crosstalk of #7 nAChR with microRNA-124 and HDAC6 ArunSundar MohanaSundaram, Thukani Sathanantham Shanmugarajan, and Velayutham Ravichandiran ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.7b00532 • Publication Date (Web): 14 Jun 2018 Downloaded from http://pubs.acs.org on June 17, 2018
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ACS Chemical Neuroscience
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3,4-Dihydroxyphenylethanol Assuages Cognitive Impulsivity in Alzheimer’s Disease by
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Attuning HPA-axis via Differential Crosstalk of α7 nAChR with microRNA-124 and
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HDAC6
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Mohanasundaram ArunSundar†, Thukani Sathanantham Shanmugarajan†*, Velayutham
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Ravichandiran‡
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†
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(VISTAS), Pallavaram, Chennai-600117, India.
Department of Pharmacology, School of Pharmaceutical Sciences, Vels University
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‡
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Kolkata, India.
Director, National Institute of Pharmaceutical Education and Research (NIPER),
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*
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Dr. TS Shanmugarajan,
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Department of Pharmacology,
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School of Pharmaceutical Sciences,
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Vels University (VISTAS),
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Chennai 600117, India
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[email protected] 20
+91-956-6049808
Corresponding author:
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Abstract:
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Cognitive impulsivity, a form of suboptimal cost-benefit decision making is an illustrious
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attribute of an array of neurodegenerative diseases including Alzheimer’s Disease (AD).
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In this study, delay discounting paradigm was used to assess the effect of 3,4-
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dihydroxyphenylethanol (DOPET) on cognitive impulsivity—in an oA42i (oligomeric
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amyloid β1–42 plus ibotenic acid) induced AD mouse model—using a non-spatial T-maze
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task. The results depicted that oA42i administration elevated cognitive impulsivity,
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whereas DOPET treatment attenuated the impulsive behavior and matched the choice
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of the sham-operated controls. In addition, DOPET treatment has ameliorated the
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anxiety-like behavior in the oA42i-challenged mice. Probing the molecular signaling
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cascades underpinning these functional ramifications in the oA42i-challenged mice
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revealed: reduced cholinergic (α7 nAChR; alpha 7 nicotinic acetylcholine receptor)
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function, dysregulated HPA-axis (manifested by amplified glucocorticoid receptor
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expression
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neuroepigenetic (microRNA-124, HDAC6 (histone deacetylase 6), and HSP90 (heat-
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shock protein 90) expressions) as well as nucleocytoplasmic (importin-α1 expression
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and nuclear ultra-architecture) continuum. Nonetheless, DOPET administration
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ameliorated these perturbations and the observations were in line with that of the sham-
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operated mice. Further validation of the results with organotypic hippocampal slice
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cultures (OHSCs) confirmed the in vivo findings. We opine that HPA-axis attunement by
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DOPET might be orchestrated through α7 nAChR-mediated pathway. Based on these
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outcomes, we posit that 3,4-dihydroxyphenylethanol might be a potential multimodal
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agent for the management of cognitive impulsivity and neuromolecular quagmire in AD.
and
plasma
corticosterone
levels),
and
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also
aberrations
in
the
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Keywords: 3,4-Dihydroxyphenylethanol, Alzheimer’s Disease, Cognitive impulsivity,
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Cholinergic receptor, HPA-axis, Decision making, HDAC6, microRNA-124
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INTRODUCTION
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Alzheimer’s Disease (AD), the most common type of dementia, is a leading cause of
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health crisis in the elderly, based on disabilities and morbidity across the globe. The
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global prevalence of AD is expected to increase from 46.8 million in 2015 to about 131.5
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million by 20501. Well above 95% of all the AD cases are non-familial and sporadic late
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onset cases2. Formation of senile β-amyloid protein plaques, neurofibrillary tau-protein
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tangles, neurodegeneration and cognitive impairment (e.g., sub-optimal decision
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making) are the pathognomonics of Morbus Alzheimer3.
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Impulsivity, a type of suboptimal cost-benefit decision making—broadly defined as the
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tendency to act prematurely without foresight—is a facet of various neurodegenerative
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diseases including AD4. It could be categorized into: (a) motor impulsivity (failure to
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control inhibitory response), and (b) cognitive impulsivity (impulsive decision making)5.
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Delay discounting (temporal discounting), an oft-reported measure of cognitive
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impulsivity, involves subjectively discounting (devaluing) the rewards (benefit) by the
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delay (cost) necessary to obtain them6. A seminal review by Vanderveldt et al.,
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concluded that delay discounting is notably pervasive and shares a commonly evolved
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decision making mechanism in humans and animal species.7
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Investigation of the neural, neurochemical and epigenetic correlates underlying delay
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discounting aids to discover potential pharmacotherapies for the management of
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impulsivity in AD. Indubitably, stress is a critical etiological factor in AD vulnerability and
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development. Heightened indices of stress engender in dysregulation of the
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hypothalamic–pituitary–adrenal (HPA) axis, which is manifested through elevated
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neurohormones, specifically glucocorticoids (GCs).8 Abnormally triggered glucocorticoid
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receptor (GR) signaling/glucocorticoid hormones–primarily cortisol in humans and
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corticosterone in rodents–have notorious implications on hippocampal structure. A study
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by Brureau et al., showed that increased GCs observed in AD could be first a
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consequence of amyloid toxicity and also HPA-axis dysfunction is linked with the
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disruption of the GR nucleocytoplasmic shuttling9. In this line, Pineau et al., reported
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that
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concentrations of corticosterone, spatial memory dysfunction and hippocampus
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apoptosis10. Hippocampus is more vulnerable to the pathological insults of amyloid beta
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and elevated GCs in AD and the repercussions include remarkable hippocampus-
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dependent memory deficits and impulsive decision making.5-7 Several lines of studies
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have demonstrated the strong association between various facets of impulsivity and
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AD4,14,15.
selective
glucocorticoid
receptor
modulators
reversed
the
high
plasma
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In a study by Abela et al., the authors proposed that targeting the hippocampal circuitry
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would be a potential strategy in the management of impulsive choice16. A recent report
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showed that β-amyloid peptide is co-localized with alpha7 nicotinic acetylcholine
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receptor (α7 nAChR) in the senile plaque17. Besides, the study reported that interaction
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between β-amyloid and α7 nAChR provokes neuronal apoptosis and diminution of the
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α7 nAChR expression; but, α7 nAChR agonists could augment the learning and
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memory potential.17 These reports imply that therapies targeting multimodal or
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combinatory strategies are required for the management of AD.
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A landmark study led by Fischer et al. accentuated that drugs regulating the
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neuroepigenetic machinery (especially histone deacetylase (HDAC) inhibitors) stave-off
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the cognitive deficits and ameliorate phenotypic outcomes in AD.18 Deficits in
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neurotrophins like BDNF (brain-derived neurotrophic factor) subsequent to epigenetic
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dysregulation is known to play a causal role in impulsive behavior.19 On the other hand,
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therapeutics targeting BDNF restoration have shown positive outcomes in the
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management of AD20,21. In congruence with these reports, our earlier study depicted
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that BDNF expression and cognitive functions were reduced in the AD mice, whereas
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hydroxytyrosol (3,4-dihydroxyphenylethanol (DOPET); a dopamine metabolite, and also
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a polyphenol from olive oil) treatment ameliorated the reduced BDNF levels and
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cognitive decline.22
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More circumstantial evidences point to the causal link between disruption of importin-
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mediated nucleocytoplasmic cargo trafficking and neuronal cell death as well as
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cognitive impairment in AD.23,24 Importin-α1 (Imp-α1; karyopherin alpha 2; KPNA2) is a
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nuclear import protein that plays a central role in the flow of genetic information and
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multitude of other cellular activities. On the other hand, Imp-α1 has been shown to
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partake in various pathological mechanisms leading to a gamut of diseases including
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cancers, neurological disorders, and viral infections. 24,25
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In this backdrop, the present study was embarked upon to investigate the putative
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beneficial effects of DOPET on the cognitive impulsivity and anxiety, dysregulated HPA
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axis, hippocampal cholinergic degeneration, and perturbations in neuroepigenetic and
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nucleocytoplasmic shuttling circuitry in an animal model of oA42i (soluble oligomeric
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amyloid β1–42 plus ibotenic acid)-induced AD. Our study marks one of the first attempts
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to untangle the neuromolecular mechanisms linking dysregulated hippocampal
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cholinergic-HPA
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neuroeconomic task in an AD mouse model.
axis
and
sub-optimal
decision-making
on
a
T-maze
based
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Organotypic hippocampal slice cultures (OHSCs) best recapitulate the complex three-
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dimensional (3D) organization of the hippocampus and this model bridges the gap
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between in vitro and in vivo models. Hence, to validate the in vivo experimental
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outcomes and to further explore the neurotoxic and neuroprotective signaling
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mechanisms of oA42i and DOPET respectively, we have used the OHSCs tool.
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RESULTS AND DISCUSSION
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DOPET treatment improved the impulsive decision making in the oA42i-
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challenged mice
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Cognitive impulsivity, an indicator of sub-optimal decision making, was significantly
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increased in the oA42i-challenged mice (Figure 2B). This inference is based on the
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observation that during phase B (i.e. blocks 4-6, post-induction testing), oA42i mice has
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depicted a reduced preference for HR, delayed by 10-s as opposed to the LR. The
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results of phases A and B were included in a three-way ANOVA, with a between-
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subjects factor of group and within-subject factors of phase and block. This analysis
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revealed a significant group x phase interaction [F2,29 = 10.12; P < 0.05]. But, no
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hindrance was observed in the optimal decision making among all the three mice
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groups in the phase A (i.e. blocks 1-3, pre-induction testing). There was no effect of
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block or any significant interaction involving block (all P > 0.40). Further analysis of the
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group x phase interaction, using analysis of simple main effects, showed that there was
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a significant group difference in phase B [F1,29 = 7.92; P < 0.05], but not in phase A (F
