Adenosine triphosphate (ATP) reduces amyloid-β protein misfolding in vitro

J Alzheimers Dis. 2014;41(2):561-74. doi: 10.3233/JAD-132300.

Abstract

Alzheimer's disease (AD) is a devastating disease of aging that initiates decades prior to clinical manifestation and represents an impending epidemic. Two early features of AD are metabolic dysfunction and changes in amyloid-β protein (Aβ) levels. Since levels of ATP decrease over the course of the disease and Aβ is an early biomarker of AD, we sought to uncover novel linkages between the two. First and remarkably, a GxxxG motif is common between both Aβ (oligomerization motif) and nucleotide binding proteins (Rossmann fold). Second, ATP was demonstrated to protect against Aβ mediated cytotoxicity. Last, there is structural similarity between ATP and amyloid binding/inhibitory compounds such as ThioT, melatonin, and indoles. Thus, we investigated whether ATP alters misfolding of the pathologically relevant Aβ42. To test this hypothesis, we performed computational and biochemical studies. Our computational studies demonstrate that ATP interacts strongly with Tyr10 and Ser26 of Aβ fibrils in solution. Experimentally, both ATP and ADP reduced Aβ misfolding at physiological intracellular concentrations, with thresholds at ~500 μM and 1 mM respectively. This inhibition of Aβ misfolding is specific; requiring Tyr10 of Aβ and is enhanced by magnesium. Last, cerebrospinal fluid ATP levels are in the nanomolar range and decreased with AD pathology. This initial and novel finding regarding the ATP interaction with Aβ and reduction of Aβ misfolding has potential significance to the AD field. It provides an underlying mechanism for published links between metabolic dysfunction and AD. It also suggests a potential role of ATP in AD pathology, as the occurrence of misfolded extracellular Aβ mirrors lowered extracellular ATP levels. Last, the findings suggest that Aβ conformation change may be a sensor of metabolic dysfunction.

Keywords: ATP; Amyloid-β; cerebrospinal fluid; metabolic dysfunction.

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphate / metabolism*
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Blotting, Western
  • Female
  • Humans
  • Magnesium / metabolism
  • Male
  • Molecular Dynamics Simulation
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Protein Folding
  • Protein Structure, Secondary

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • Magnesium