Metal mixture-induced non-transgenic animal model of Alzheimer’s disease: Pros and cons

Alzheimer’s disease (AD) is a multifaceted and heterogeneous age-related disease and represents the most common cause of dementia among the elderly. Over the past two decades, transgenic models of AD appreciably contribute to the understanding of the molecular mechanisms involved in the onset and progression of AD. However, transgenic models generally identify with the familial form of AD that accounts for just 5% of AD cases. Thus, non-transgenic models are also essential to thoroughly understand AD pathophysiology. Environmental exposure to heavy metals has been linked to the pathogenesis of the non-familial, sporadic form of AD. This review summarizes our previously published research that showed a mixture of heavy metals, i.e. Arsenic (As), cadmium (Cd) and lead (Pb) at environmentally relevant doses induced AD-parameters and AD-like pathology in the young rats. Our previous findings suggest that the amyloid beta-42 (Aβ1-42) levels in the As+Cd+Pbmixture treated Postnatal-90 day rat brain were comparable with the intracerebroventricular Aβ1-42 infusion rat model, which is wellestablished non-transgenic model of AD. Additionally, As+Cd+Pb-mixtureinduced Aβ and amyloid precursor protein could be attenuated by known AD-directed drugs, memantine, and donepezil. These findings helped us to conclude that As+Cd+Pb-treated animals could be utilized as a non-transgenic model of AD. This review also summarizes the merits of a nontransgenic animal model of AD, generated through environmental doses of As, Cd and Pb-mixture and its demerits. Introduction Alzheimer’s disease (AD) is one of the most common forms of progressive dementia globally. According to the recent report of Alzheimer’s Association, approximately 4.5 million people in the United States currently suffering from AD.1 In India, more than 4 million people are affected by some form of dementia.1 Extracellular senile plaques are considered to be one of the major neuropathological hallmarks of AD.2 The key protein component of extracellular plaques is the amyloid beta (Aβ), a 39 to 43 amino acid peptide, cleaved from amyloid precursor protein (APP) by β-secretase and a putative γ (gamma)-secretase.3 Many lines of evidence suggest that abnormal deposition of neurotoxic Aβ is associated with a decline in memory and learning ability of affected individuals and contribute to the pathogenesis of AD.4 Substantial research has been carried out to develop animal models that exhibit characteristic neuropathological features of AD.5 Most of the animal models employed in the AD-directed drug screening include transgenic mice that over-express mutant APP or presenilin genes. However, these transgenic models are developed by genetic manipulation and do not mimic all facets of human AD such as extensive neuronal loss, Aβ plaque formation or significant memory impairment.6,7 Furthermore, transgenic mice do not represent a genuine model for sporadic AD.8 Transgenic models are only suitable for studying the familial pattern of AD with genetic links and represent about 5% of all Alzheimer’s cases.9 A detailed description regarding the limitations of these models is given in Table 1. Therefore, more relevant models bearing AD-like characteristics are essential.10 Non-transgenic animal models provide alternative approaches to the more widely used transgenic AD models. These models represent the sporadic AD that accounts for 95% of cases.10 Beside Aβ deposition, these models also manifest considerable oxidative stress, gliosis, inflammatory reactivity and cognitive impairment.11 Therefore, these models exhibit the complete pathophysiology of AD. Additionally, this type of model is morally accepted by the public and scientific community.10 However, non-transgenic method of infusing Aβ peptide12 or streptozotocin13 involves the disadvantage of intracerebroventricular delivery. Moreover, none of the present models are reported to render early-onset AD symptoms. Heavy metals contamination and their role in Alzheimer’s disease Majority of the AD cases (approximately 90%) are sporadic, where environmental pollutants act as important risk factors.14 Environmental exposure to heavy metals such as lead (Pb), mercury (Hg), aluminium (Al), cadmium (Cd) and arsenic (As) have been reported to be involved in AD.15-18 Arsenic, Cd and Pb are among the leading toxicants detected in the environment globally.19,20 These metals have been linked to developmental neurotoxicity and various neurodegenerative disorders.21,22 As+Cd+Pb-mixture treated nontransgenic Alzheimer’s disease model We established a non-transgenic animal model of AD, induced by environmentally relevant doses of heavy metal mixture Correspondence: Anushruti Ashok, Department of Pathology, UC Davis MIND Institute, Sacramento, California, USA. Tel.: 916.477.5725. E-mail: anushruti.ashok27@gmail.com aashok@ucdavis.edu