The 28-amino acid form of an APLP1-derived Abeta-like peptide is a surrogate marker for Abeta42 production in the central nervous system.
Surrogate markers for the Alzheimer disease (AD)-associated 42-amino acid form of amyloid-beta (Abeta42) have been sought because they may aid in the diagnosis of AD and for clarification of disease pathogenesis. Here, we demonstrate that human cerebrospinal fluid (CSF) contains three APLP1-derived Abeta-like peptides (APL1beta) that are generated by beta- and gamma-cleavages at a concentration of approximately 4.5 nM. These novel peptides, APL1beta25, APL1beta27 and APL1beta28, were not deposited in AD brains. Interestingly, most gamma-secretase modulators (GSMs) and familial AD-associated presenilin1 mutants that up-regulate the relative production of Abeta42 cause a parallel increase in the production of APL1beta28 in cultured cells. Moreover, in CSF from patients with pathological mutations in presenilin1 gene, the relative APL1beta28 levels are higher than in non-AD controls, while the relative Abeta42 levels are unchanged or lower. Most strikingly, the relative APL1beta28 levels are higher in CSF from sporadic AD patients (regardless of whether they are at mild cognitive impairment or AD stage), than those of non-AD controls. Based on these results, we propose the relative level of APL1beta28 in the CSF as a candidate surrogate marker for the relative level of Abeta42 production in the brain.
Yanagida
Kanta
K
Psychiatry, Department of Integrated Medicine, Division of Internal Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
Okochi
Masayasu
M
Tagami
Shinji
S
Nakayama
Taisuke
T
Kodama
Takashi S
TS
Nishitomi
Kouhei
K
Jiang
Jingwei
J
Mori
Kohji
K
Tatsumi
Shin-Ichi
S
Arai
Tetsuaki
T
Ikeuchi
Takeshi
T
Kasuga
Kensaku
K
Tokuda
Takahiko
T
Kondo
Masaki
M
Ikeda
Masaki
M
Deguchi
Kentaro
K
Kazui
Hiroaki
H
Tanaka
Toshihisa
T
Morihara
Takashi
T
Hashimoto
Ryota
R
Kudo
Takashi
T
Steiner
Harald
H
Haass
Christian
C
Tsuchiya
Kuniaki
K
Akiyama
Haruhiko
H
Kuwano
Ryozo
R
Takeda
Masatoshi
M
D000328:Adult; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000175:diagnosis*; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000032:analysis / Q000134:cerebrospinal fluid* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis / Q000134:cerebrospinal fluid* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000032:analysis / Q000134:cerebrospinal fluid* / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics
C489697:APLP1 protein, human; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human