Circulating amyloid-beta peptide crosses the blood-brain barrier in aged monkeys and contributes to Alzheimer's disease lesions

Vascul Pharmacol. 2002 Jun;38(6):303-13. doi: 10.1016/s1537-1891(02)00198-2.


1. We studied cerebrovascular sequestration and blood-brain barrier (BBB) permeability to [125I]- or [123I]-labeled amyloid-beta peptides (A beta) in aged rhesus and aged squirrel monkey, the nonhuman primate models of cerebral beta-amyloidosis and cerebrovascular amyloid angiopathy (CAA), respectively. 2. In aged rhesus, the half-time of elimination of [125I]A beta 1-40, t1/2e, was faster by 1.34 h, the systemic clearance, Clss, increased by 4.21 ml/min/kg and the mean residence time of intact peptide in the circulation shortened by 2 h. 3. Cerebrovascular sequestration of [125I]A beta 1-40 was significant in aged squirrel monkey (20.8 ml/g x 10(2)), but undetectable in the rhesus. 4. The permeability surface area product, PS, for [14C]inulin was low in both species (0.11-0.18 ml/g/s x 10(6)) indicating an intact barrier. 5. The BBB permeability to A beta 1-40 was 34.8- and 13.7-fold higher than for [14C]inulin in aged squirrel and rhesus, respectively, suggesting a specialized A beta transport across the BBB. 6. The single photon computed emission tomography studies confirmed a saturable [123I]A beta 1-40 transport at the BBB in primates (Km = 40 nM). 7. Brain autoradiographic analysis of [125I]A beta 1-42 or [125I]A beta 1-40 after intracarotid infusions of radiotracers confirmed co-localization of the signal with A beta-immunoreactive plaques in rhesus monkeys. 8. Metabolism of [125I]A beta 1-40 in brain and plasma was slower in aged squirrel compared to aged rhesus, by 2.9- and 2.6-fold, respectively. 9. Thus, transport of circulating A beta across the BBB contributes to brain parenchymal accumulation of amyloid in aged nonhuman primates. Negligible capillary binding, rapid systemic and brain degradation, and accelerated body elimination of blood-borne A beta, may prevent the development of CAA in rhesus in contrast to squirrel monkeys.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Aging / physiology*
  • Alzheimer Disease / blood*
  • Alzheimer Disease / etiology
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / blood*
  • Amyloid beta-Peptides / pharmacokinetics
  • Amyloidosis / blood*
  • Amyloidosis / complications
  • Amyloidosis / pathology
  • Animals
  • Blood-Brain Barrier*
  • Cerebral Amyloid Angiopathy / blood
  • Cerebral Amyloid Angiopathy / complications
  • Cerebral Amyloid Angiopathy / pathology
  • Cerebrovascular Circulation
  • Disease Models, Animal
  • Humans
  • Immunohistochemistry
  • Macaca mulatta
  • Microcirculation
  • Peptide Fragments / blood*
  • Peptide Fragments / pharmacokinetics
  • Saimiri
  • Tomography, Emission-Computed, Single-Photon


  • Amyloid beta-Peptides
  • Peptide Fragments
  • amyloid beta-protein (1-40)