Substitution at codon 22 reduces clearance of Alzheimer’s amyloid-β peptide from the cerebrospinal fluid and prevents its transport from the central nervous system into blood

• Published in: Neurobiology of aging 2002-05, Vol.23 (3), p.405-412
• Main Authors: Monro, O.R., Mackic, J.B., Yamada, S., Segal, M.B., Ghiso, J., Maurer, C., Calero, M., Frangione, B., Zlokovic, B.V.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Amino Acid Sequence; Amino Acid Substitution - genetics; Amyloid beta-Peptides - blood; Amyloid beta-Peptides - cerebrospinal fluid; Amyloid-β peptide; Animals; Biological and medical sciences; Blood-Brain Barrier; Brain - metabolism; Cerebrovascular Circulation - genetics; Choroid plexus; Choroid Plexus - metabolism; Codon - genetics; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dutch mutant; Female; Guinea Pigs; Male; Medical sciences; Molecular Sequence Data; Neurology; Peptide Fragments - blood; Peptide Fragments - cerebrospinal fluid; Perfusion; Point Mutation; Protein Transport - genetics; Ventriculo-Cisternal Perfusion
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/S0197-4580(01)00317-7

A point mutation of G to C at codon 693 of the amyloid-beta (Aβ) precursor protein gene results in Glu to Gln substitution at position 22 of the Aβ (AβQ22) associated with hereditary cerebrovascular amyloidosis with hemorrhage Dutch type. Factors that regulate AβQ22 levels in the central nervous system (CNS) are largely unknown. By using ventriculo-cisternal perfusion technique in guinea pigs, we demonstrated that clearance from the cerebrospinal fluid and transport from the CNS to blood of [ 125I]-AβQ22 (1 nM) were reduced by 36% and 52%, respectively, in comparison to the wild type Aβ 1–40 peptide. In contrast to significant uptake and transport of Aβ 1–40 across the brain capillaries and leptomeningeal vessels, AβQ22 was not taken up at these CNS vascular transport sites, which was associated with its 53% greater accumulation in the brain. The CNS clearance of Aβ 1–40 was half-saturated at 23.6 nM; AβQ22 had about 6.8-fold less affinity for the CNS efflux transporters and its elimination relied mainly on transport across the choroid plexus. Thus, the Dutch mutation impairs elimination of Aβ from brain by reducing its rapid transport across the blood-brain barrier and the vascular drainage pathways, which in turn may result in accumulation of the peptide around the blood vessels and in brain.