Current Alzheimer Research   Send Orders for Reprints to reprints@benthamscience.ae 1114 Current Alzheimer Research, 2018, 15, 1114-1122 RESEARCH ARTICLE Influence of Early Life Lead (Pb) Exposure on α α -Synuclein, GSK-3β and Caspase-3 Mediated Tauopathy: Implications on Alzheimer’s Disease Syed Waseem Bihaqi 1,4 , Bothaina Alansi 2 , Anwar M. Masoud 5 , Foqia Mushtaq 2 , Gehad M. Subaiea 1 and Nasser H. Zawia 2,3,4,* 1 Department of Pharmacology and Toxicology, College of Pharmacy, University of Hail, Hail, Kingdom of Saudi Ara- bia; 2 Department of Biomedical and Pharmaceutical Sciences, 3 Interdisciplinary Neuroscience Program; 4 George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USA; 5 Biochemical Technology Program, Faculty of Applied Science, Thamar University, Thamar, Yemen A R T I C L E H I S T O R Y Received: March 07, 2018 Revised: June 21, 2018 Accepted: July 15, 2018 DOI: 10.2174/1567205015666180801095925 Abstract: Background: Previously we have shown that developmental exposure to the heavy metal lead (Pb) resulted in latent cognitive impairment, upregulation of biomarkers and pathology associated with both the tau and amyloid pathways, however, the impact on Alpha Synuclein (α-Syn) and its relationship to these pathways and their connection to cognitive performance warrant further elucidation. Objective: The present study determined the impact of developmental Pb exposure on the α-Syn path- ways in a mouse model knock-out (KO) for murine tau gene and in differentiated human neuroblastoma SHSY5Y cell line exposed to a series of Pb concentrations. Methods: Western blot analysis and RT-PCR were used to assess the levels of intermediates in the tau and α-Syn pathways following postnatal Pb exposure on aged mice lacking tau gene and in differenti- ated SHSY5Y cells on day 3 and day 6 after the Pb exposure had ceased. Result: Early life Pb exposure is accompanied by latent up-regulation in α-Syn in these mice. Further- more, prior exposure to Pb in-vitro also resulted in an increase in α-Syn, its phosphorylated forms, as well as an increase in glycogen synthase kinase 3β (GSK-3β) and Caspase-3. Conclusion: An environmental agent can act as a latent inducer of both α-Syn and associated kinases that are involved in tau hyperphosphorylation and may allude to the interactive nature of these two neu- rodegenerative pathways. Keywords: Alzheimer’s disease, α-Syn, GSK3β, Caspase-3, lead (Pb), tau protein. 1. INTRODUCTION Despite having variance in clinical and pathological characteristics, mounting evidence indicates that there is a noticeable overlap between tauopathies and synuclei- nopathies, emphasizing the notion that these diseases may be mechanistically linked [1]. In the brain, α-Synuclein (α-Syn) is present in various nuclei, but its presence in high concen- trations in the neocortex, hippocampus, and substantia nigra, is reminiscent of those affected with Alzheimer’s disease (AD) [2]. Accumulating evidences revealed that 50% of AD patients display a third pathological protein aggregate namely Lewy bodies (LBs) composed of phosphorylated α- Syn (p-α-Syn) [3, 4]. Also, 50% of AD patients who display clinically detected extrapyramidal signs, feature extensive α- Syn pathology co-localized in the substantia nigra with phosphorylated tau (p-tau) [5]. α-Syn has also been found to *Address correspondence to this author at the Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, 02881, USA; Tel: +1-401-874-2663; Fax: +1-401-874-5491; E-mail: nzawia@uri.edu bind to tau, a microtubule-associated protein (MAP) that undergoes pathogenic phosphorylation in AD [6]. This α- Syn/tau association seems functional because it leads to en- hanced protein kinase A (PKA) mediated tau phosphoryla- tion [7]. Abundant information exists regarding the pathological aspects, the molecular and cellular interplay between α-Syn and p-tau leading to their pathological co-deposition [8]. However, the precise nature of their relationship remains obscure. Studies have found that under pathological condi- tions, α-Syn is rendered insoluble, which eventually self- aggregates and accumulates into LBs [5, 9]. Similar to α- Syn, tau is a highly soluble protein but under pathological condition, it becomes insoluble by hyperphosphorylation at specific sites which leads to conformational modifications that result in accumulation of the proteins as neurofibrillary tangles (NFTs) [10]. Reports from Alzheimer’s Disease Neu- roimaging Initiative (ADNI) found increased α-Syn levels in cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD, and demonstrated correlations between CSF levels of α-Syn and the neuronal damage 1875-5828/18 $58.00+.00 © 2018 Bentham Science Publishers