Activation of beta2-adrenergic receptor stimulates gamma-secretase activity and accelerates amyloid plaque formation

Nat Med. 2006 Dec;12(12):1390-6. doi: 10.1038/nm1485. Epub 2006 Nov 19.


Amyloid plaque is the hallmark and primary cause of Alzheimer disease. Mutations of presenilin-1, the gamma-secretase catalytic subunit, can affect amyloid-beta (Abeta) production and Alzheimer disease pathogenesis. However, it is largely unknown whether and how gamma-secretase activity and amyloid plaque formation are regulated by environmental factors such as stress, which is mediated by receptors including beta(2)-adrenergic receptor (beta(2)-AR). Here we report that activation of beta(2)-AR enhanced gamma-secretase activity and thus Abeta production. This enhancement involved the association of beta(2)-AR with presenilin-1 and required agonist-induced endocytosis of beta(2)-AR and subsequent trafficking of gamma-secretase to late endosomes and lysosomes, where Abeta production was elevated. Similar effects were observed after activation of delta-opioid receptor. Furthermore, chronic treatment with beta(2)-AR agonists increased cerebral amyloid plaques in an Alzheimer disease mouse model. Thus, beta(2)-AR activation can stimulate gamma-secretase activity and amyloid plaque formation, which suggests that abnormal activation of beta(2)-AR might contribute to Abeta accumulation in Alzheimer disease pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / biosynthesis
  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • Cyclic AMP / physiology
  • Endocytosis
  • Enzyme Activation
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Oligopeptides / physiology
  • Plaque, Amyloid / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, beta-2 / metabolism
  • Receptors, Adrenergic, beta-2 / physiology*


  • Amyloid beta-Peptides
  • Oligopeptides
  • PS1 antigen
  • Receptors, Adrenergic, beta-2
  • Cyclic AMP
  • Amyloid Precursor Protein Secretases