Exposure to As-, Cd-, and Pb-mixture induces Aβ, amyloidogenic APP processing and cognitive impairments via oxidative stress-dependent neuroinflammation in young rats

Toxicol Sci. 2015 Jan;143(1):64-80. doi: 10.1093/toxsci/kfu208. Epub 2014 Oct 6.


Environmental pollutants act as risk factors for Alzheimer's disease (AD), mainly affecting the aging population. We investigated early manifestations of AD-like pathology by a mixture of arsenic (As), cadmium (Cd), and lead (Pb), reported to impair neurodevelopment. We treated rats with As+Cd+Pb at their concentrations detected in groundwater of India, ie, 0.38, 0.098, and 0.22 ppm or 10 times of each, respectively, from gestation-05 to postnatal day-180. We identified dose-dependent increase in amyloid-beta (Aβ) in frontal cortex and hippocampus as early as post-weaning. The effect was strongly significant during early-adulthood, reaching levels comparable to an Aβ-infused AD-like rat model. The metals activated the proamyloidogenic pathway, mediated by increase in amyloid precursor protein (APP), and subsequent beta secretase (BACE) and presenilin (PS)-mediated APP-processing. Investigating the mechanism of Aβ-induction revealed an augmentation in oxidative stress-dependent neuroinflammation that stimulated APP expression through interleukin-responsive-APP-mRNA 5'-untranslated region. We then examined the effects of individual metals and binary mixtures in comparison with the tertiary. Among individual metals, Pb triggered maximum induction of Aβ, whereas individual As or Cd had a relatively non-significant effect on Aβ despite enhanced APP, owing to reduced induction of BACE and PS. Interestingly, when combined the metals demonstrated synergism, with a major contribution by As. The synergistic effect was significant and consistent in tertiary mixture, resulting in the augmentation of Aβ. Eventually, increase in Aβ culminated in cognitive impairments in the young rats. Together, our data demonstrate that exposure to As+Cd+Pb induces premature manifestation of AD-like pathology that is synergistic, and oxidative stress and inflammation dependent.

Keywords: AD-like pathology; early onset; environment; heavy metals; synergistic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions
  • Age Factors
  • Alzheimer Disease / chemically induced*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / physiopathology
  • Alzheimer Disease / psychology
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Arsenites / toxicity*
  • Aspartic Acid Endopeptidases / metabolism
  • Behavior, Animal / drug effects*
  • Cadmium Chloride / toxicity*
  • Cells, Cultured
  • Cognition / drug effects*
  • Cognition Disorders / chemically induced*
  • Cognition Disorders / metabolism
  • Cognition Disorders / physiopathology
  • Cognition Disorders / psychology
  • Drug Synergism
  • Female
  • Frontal Lobe / drug effects*
  • Frontal Lobe / metabolism
  • Frontal Lobe / physiopathology
  • Gestational Age
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Inflammation Mediators / metabolism
  • Male
  • Organometallic Compounds / toxicity*
  • Oxidative Stress / drug effects*
  • Pregnancy
  • Prenatal Exposure Delayed Effects
  • Presenilins / metabolism
  • RNA, Messenger / metabolism
  • Rats, Wistar
  • Risk Assessment
  • Sodium Compounds / toxicity*
  • Transcription, Genetic
  • Water Pollutants, Chemical / toxicity*


  • 5' Untranslated Regions
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Arsenites
  • Inflammation Mediators
  • Organometallic Compounds
  • Presenilins
  • RNA, Messenger
  • Sodium Compounds
  • Water Pollutants, Chemical
  • sodium arsenite
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, rat
  • Cadmium Chloride
  • lead acetate