Substitution at codon 22 reduces clearance of Alzheimer's amyloid-beta peptide from the cerebrospinal fluid and prevents its transport from the central nervous system into blood.
A point mutation of G to C at codon 693 of the amyloid-beta (Abeta) precursor protein gene results in Glu to Gln substitution at position 22 of the Abeta (AbetaQ22) associated with hereditary cerebrovascular amyloidosis with hemorrhage Dutch type. Factors that regulate AbetaQ22 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 [(125)I]-AbetaQ22 (1 nM) were reduced by 36% and 52%, respectively, in comparison to the wild type Abeta(1-40) peptide. In contrast to significant uptake and transport of Abeta(1-40) across the brain capillaries and leptomeningeal vessels, AbetaQ22 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 Abeta(1-40) was half-saturated at 23.6 nM; AbetaQ22 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 Abeta 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.
Monro
O R
OR
Department of Neurosurgery, University of Southern California, Los Angeles, CA, USA.
Mackic
J B
JB
Yamada
S
S
Segal
M B
MB
Ghiso
J
J
Maurer
C
C
Calero
M
M
Frangione
B
B
Zlokovic
B V
BV
D000544:Alzheimer Disease / Q000235:genetics*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000097:blood* / Q000134:cerebrospinal fluid*; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000235:genetics*; D002831:Choroid Plexus / Q000378:metabolism; D003062:Codon / Q000235:genetics*; D005260:Female; D006168:Guinea Pigs; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000097:blood* / Q000134:cerebrospinal fluid*; D010477:Perfusion; D017354:Point Mutation; D021381:Protein Transport / Q000235:genetics
D016229:Amyloid beta-Peptides; D003062:Codon; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)