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

1. We studied cerebrovascular sequestration and blood–brain barrier (BBB) permeability to [125I]- or [123I]-labeled amyloid-β peptides (Aβ) in aged rhesus and aged squirrel monkey, the nonhuman primate models of cerebral β-amyloidosis and cerebrovascular amyloid angiopathy (CAA), respectively.2. In aged rhesus, the half-time of elimination of [125I]Aβ1–40, 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]Aβ1−40 was significant in aged squirrel monkey (20.8 ml/g×102), 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×106) indicating an intact barrier.5. The BBB permeability to Aβ1−40 was 34.8- and 13.7-fold higher than for [14C]inulin in aged squirrel and rhesus, respectively, suggesting a specialized Aβ transport across the BBB.6. The single photon computed emission tomography studies confirmed a saturable [123I]Aβ1–40 transport at the BBB in primates (Km=40 nM).7. Brain autoradiographic analysis of [125I]Aβ1–42 or [125I]Aβ1−40 after intracarotid infusions of radiotracers confirmed co-localization of the signal with Aβ-immunoreactive plaques in rhesus monkeys.8. Metabolism of [125I]Aβ1−40 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 Aβ 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 Aβ, may prevent the development of CAA in rhesus in contrast to squirrel monkeys. [Copyright &y& Elsevier]