Non-Phosphorylated Tau in Cerebrospinal Fluid is a Marker of Alzheimer's Disease Continuum in Young Urbanites Exposed to Air Pollution

Lilian Calderón-Garcidueñas, Partha S. Mukherjee, Katharina Waniek, Max Holzer, Chih Kai Chao, Charles Thompson, Rubén Ruiz-Ramos, Ana Calderón-Garcidueñas, Maricela Franco-Lira, Rafael Reynoso-Robles, Angélica Gónzalez-Maciel, Ingolf Lachmann

Research output: Contribution to journalArticlepeer-review

Abstract

Long-term exposure to fine particulate matter (PM 2.5) and ozone (O 3) above USEPA standards is associated with Alzheimer's disease (AD) risk. Metropolitan Mexico City (MMC) children exhibit subcortical pretangles in infancy and cortical tau pre-tangles, NFTs, and amyloid phases 1-2 by the 2nd decade. Given their AD continuum, we measured in 507 normal cerebrospinal fluid (CSF) samples (MMC 354, controls 153, 12.82±6.73 y), a high affinity monoclonal non-phosphorylated tau antibody (non-P-Tau), as a potential biomarker of AD and axonal damage. In 81 samples, we also measured total tau (T-Tau), tau phosphorylated at threonine 181 (P-Tau), amyloid-β 1-42, BDNF, and vitamin D. We documented by electron microscopy myelinated axonal size and the pathology associated with combustion-derived nanoparticles (CDNPs) in anterior cingulate cortex white matter in 6 young residents (16.25±3.34 y). Non-P-Tau showed a strong increase with age significantly faster among MMC versus controls (p=0.0055). Aβ 1 - 42 and BDNF concentrations were lower in MMC children (p=0.002 and 0.03, respectively). Anterior cingulate cortex showed a significant decrease (p=<0.0001) in the average axonal size and CDNPs were associated with organelle pathology. Significant age increases in non-P-Tau support tau changes early in a population with axonal pathology and evolving AD hallmarks in the first two decades of life. Non-P-Tau is an early biomarker of axonal damage and potentially valuable to monitor progressive longitudinal changes along with AD multianalyte classical CSF markers. Neuroprotection of young urbanites with PM 2.5 and CDNPs exposures ought to be a public health priority to halt the development of AD in the first two decades of life.

Original languageEnglish
Pages (from-to)1437-1451
Number of pages15
JournalJournal of Alzheimer's Disease
Volume66
Issue number4
DOIs
StatePublished - 2018

Keywords

  • Alzheimer's disease
  • Aβ 1-42
  • BDNF
  • Mexico City
  • PM 2.5
  • PrP C
  • Vitamin D
  • Wallerian degeneration
  • air pollution
  • axonal damage
  • cerebrospinal fluid
  • children
  • combustion-derived nanoparticles
  • insulin
  • leptin
  • non-phosphorylated tau
  • white matter

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