The amyloid-β isoform pattern in cerebrospinal fluid in familial PSEN1             M139T- and L286P-associated Alzheimer's disease.
There are several familial forms of Alzheimer's disease (AD) most of which             are caused by mutations in the genes that encode the presenilin enzymes involved             in the production of amyloid-β (Aβ) from the amyloid precursor protein (APP).             In AD, Aβ forms fibrils that are deposited in the brain as plaques. Much of the             fibrillar Aβ found in the plaques consists of the 42 amino acid form of Aβ (Aβ1-42)             and it is now widely accepted that Aβ is related to the pathogenesis of AD and             that Aβ may both impair memory and be neurotoxic. In human cerebrospinal fluid             (CSF) several C- and N-terminally truncated Aβ isoforms have been detected and             their relative abundance pattern is thought to reflect the production and clearance             of Aβ. By using immunoprecipitation and mass spectrometry, we have previously             demonstrated that carriers of the familial AD (FAD)-associated PSEN1 A431E mutation             have low CSF levels of C-terminally truncated Aβ isoforms shorter than Aβ1-40.             Here we replicate this finding in symptomatic carriers of the FAD-causing PSEN1             L286P mutation. Furthermore, we show that preclinical carriers of the PSEN1 M139T             mutation may overexpress Aβ1-42 suggesting that this particular mutation may cause             AD by stimulating γ-secretase-mediated cleavage at amino acid 42 in the Aβ sequence.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. erik.portelius@neuro.gu.se
Erik
E
Portelius
Juan
J
Fortea
Jose Luis
JL
Molinuevo
Mikael K
MK
Gustavsson
Ulf
U
Andreasson
Raquel
R
Sanchez-Valle
D000328:Adult; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D019943:Amino Acid Substitution; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid* / Q000737:chemistry; D006801:Humans; D047468:Immunoprecipitation; D009154:Mutation; D010446:Peptide Fragments / Q000134:cerebrospinal fluid* / Q000737:chemistry; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000134:cerebrospinal fluid / Q000737:chemistry; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D016229:Amyloid beta-Peptides; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D020033:Protein Isoforms; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases