Arsenic Exposure Contributes to the Bioenergetic Damage in an

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Arsenic exposure contributes to the bioenergetic damage in an Alzheimer's disease model Sandra Aurora Niño, Adriana Morales-Martínez, Erika Chi-Ahumada, Leticia Carrizales, Roberto Salgado Delgado, Francisca Pérez-Severiano, Sofía Díaz-Cintra, María Esther Jiménez-Capdeville, and Sergio Zarazua ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.8b00278 • Publication Date (Web): 24 Aug 2018 Downloaded from http://pubs.acs.org on August 25, 2018

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ACS Chemical Neuroscience

Arsenic exposure contributes to the bioenergetic damage in an Alzheimer's disease model Sandra Aurora Niñoa, Adriana Morales-Martínezb, Erika Chi-Ahumadac, Leticia Carrizalesd, Roberto Salgado-Delgadoe, Francisca Pérez-Severianob, Sofía DíazCintraf, María E. Jiménez-Capdevillec, Sergio Zarazúaa a

Laboratorio de Neurotoxicología, Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, Av. Manuel Nava 6, C.P 78210, San Luis Potosí, S.L.P, México b

Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”, Insurgentes Sur 3877, C.P 14269, México D.F., México

c

Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de San Luis Potosi, Av. Venustiano Carranza 2405, C.P 78210, San Luis Potosí, S.L.P, México d

Centro de Investigación Aplicada en Ambiente y Salud, CIACYT, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, Av. Venustiano Carranza 2405, C.P 78210, San Luis Potosí, S.L.P., México

e

Facultad de Ciencias, Universidad Autónoma de San Luis Potosí, Av. Salvador Nava Martínez S/N, C.P 78290, San Luis Potosí, S.L.P, Mexico

f

Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, C.P 76230, México.

Sergio Zarazúa Laboratorio de Neurotoxicología Facultad de Ciencias Químicas Av.Manuel Nava 6, CP 78210; San Luis Potosí, S.L.P., México Phone: +52 (444) 826 2300 Ext. 6425 E-mail: [email protected]

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Abstract Worldwide, every year there is an increase in the number of people exposed to inorganic arsenic (iAs) via drinking water. Human populations present impaired cognitive function as a result of prenatal and childhood iAs exposure, while studies in

animal models

demonstrate

neurobehavioral deficits

accompanied

by

neurotransmitter, protein and enzyme alterations. Similar impairments have been observed in close association with Alzheimer´s disease (AD). In order to determine whether iAs promotes the pathophysiological progress of AD, we used the 3xTgAD mouse model. Mice were exposed to iAs in drinking water from gestation until 6 months (As-3xTgAD group) and compared with control animals without arsenic (3xTgAD group). We investigated the behavior phenotype on a test battery (circadian rhythm, locomotor behavior, Morris water maze and contextual fear conditioning). Adenosine triphosphate (ATP), reactive oxygen species, lipid peroxidation and respiration rates of mitochondria were evaluated and antioxidant components detected by immunoblots and immunohistochemical studies were performed to reveal AD markers. As-3xTgAD displayed alterations in their circadian rhythm and exhibited longer freezing time and escape latencies compared to the control group. The bioenergetic profile revealed decreased ATP levels accompanied by the decline of complex I, and an oxidant state in the hippocampus. On the other hand, the cortex showed no changes of oxidant stress and complex I, however, the antioxidant response was increased. Higher immunopositivity to amyloid isoforms and to phosphorylated tau was observed in frontal cortex and hippocampus of exposed animals. In conclusion, mitochondrial dysfunction may be one of the triggering factors through which chronic iAs exposure exacerbates brain AD-like pathology.


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Abbreviations 3xTgAD, triple-transgenic Alzheimer’s disease model; iAs, inorganic arsenic; Aβ, amyloid beta; AD, Alzheimer's disease; ADP, adenosine diphosphate; ATP, adenosine triphosphate; APP, Amyloid precursor protein; CNS, central nervous system; LPx, lipid peroxidation; MWM, Morris water-maze; RCR, respiratory control ratio; ROS, reactive oxygen species; SOD, superoxide dismutase; NFTs, neurofibrillary tangles; PHF, paired helical filaments; ppm, parts per million; VDAC, Voltage-dependent anion channel Keywords: arsenic, neurodegeneration, mitochondrial dysfunction, Alzheimer’s disease, protein aggregation, behavioral changes, oxidative stress.



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1. Introduction Inorganic arsenic (iAs) is a widely distributed, naturally occurring metalloid in the Earth’s crust. Current human arsenic exposure occurs mostly through drinking water since arsenic compounds become mobilized from rocks and soil into groundwater

1,2.

An accidental severe exposure that took place in the mid

twentieth-century in Japan, through contaminated powder milk, tragically revealed the high neurotoxicity of iAs3, especially when exposure happens during development. By the turn of the twenty-first century, epidemiological studies in iAsexposed populations around the world gradually established that childhood is a critical period where even low-level iAs exposure has deleterious consequences for the developing nervous system.4,5,6,7,8 Through these studies it became clear that intellectual dysfunction is the main risk of early–life chronic iAs exposure, because it appears at exposure levels well below those of other toxic iAs effects, such diarrhea, vascular alterations, skin damage and cancer, among others.9,10,11 Behavioral deficits, learning deficiency and changes of neurotransmitter release and its receptors have been traced back to basic cellular functions affected by either iAs or its metabolites.12,13,14 In this context, iAs exposure has been proposed as an important environmental factor that could contribute to triggering neurodegenerative diseases as Alzheimer´s disease (AD) later in life.15,16,17 Although the initial hypothesis was based mostly in epidemiological evidence linking chronic environmental iAs exposure with cognitive decline in geriatric populations, it is gaining support the opinion that the progressive cognitive dysfunction that characterize AD bears biochemical and morphological similarities to the neurotoxic process elicited by iAs exposure.18,19 Alzheimer`s disease (AD) is the most frequent neurodegenerative disease and represents the main cause of dementia, accounting for 60–80% of cases (Alzheimer's Association, 2016). Brains affected by AD are mainly characterized by oxidative damage, activated microglia and altered proteostasis.20,21 Indeed, AD is considered the prototypic proteinopathy, since in autopsied brain tissue of AD 4 ACS Paragon Plus Environment

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patients there is an universal presence of extracellular amyloid plaques composed of various beta-amyloid (Aβ) peptides22,23, resulting from the cleavage of the amyloid precursor protein (APP) and by intracellular neurofibrillary tangles (NFT) containing hyperphosphorylated tau protein.24,25 In this context, it has been demonstrated that low-level arsenic exposure in the rat, favors the expression of APP and induces a rise of Aβ (1-42) cleaved by increased BACE1 enzymatic activity accompanied by behavioral deficits.26 It would be of great interest to know whether these alterations are related to oxidative imbalance, as a classical mechanism of iAs neurotoxicity, and if behavioral deficits are actually associated to the proteinopathy that characterizes AD. A wide range of animal models has been employed to investigate the origin of AD or disease-modifying agents.27,28,29 Especially, histopathological characteristics of the disease have been reproduced.30 Recently, a triple transgenic mouse (3xTgAD) harboring the human APPSwe-PS1M146V-TauP301L gene mutations was developed. These animals, display accumulation of both intracellular Aβ and tau in an age-dependent manner inside the cortex, hippocampus, and amygdala and to a lower degree, in the brainstem.31,32 We employed this animal model in order to test the hypothesis that iAs exposure exacerbates the pathophysiological progress of AD. For this purpose, mice were exposed to iAs from prenatal development until the age of six months (As-3xTgAD). These animals performed a battery of behavioral tasks previous to the quantification of mitochondrial respiration, oxidative status as well as analysis of the presence of Aβ and phosphorylated tau in brain regions, in order to demonstrate the effects of iAs exposure.



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2. Results and Discussion 2.1 Characterization of the experimental model after iAs exposure No negative effects on the general health of the mice were observed; neither physical appearance changes nor body weight loss was found as a consequence of iAs exposure. Brain iAs content of control and exposed animals was quantified by means of atomic fluorescence spectrometry. Student’s t-test confirmed a significant increase of iAs levels (p

Arsenic Exposure Contributes to the Bioenergetic Damage in an

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