Distinct patterns of APP processing in the CNS in autosomal-dominant and sporadic Alzheimer disease.
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Distinct patterns of APP processing in the CNS in autosomal-dominant and sporadic Alzheimer disease. / Pera, Marta; Alcolea, Daniel; Sánchez-Valle, Raquel; Guardia-Laguarta, Cristina; Colom-Cadena, Martí; Badiola, Nahuai; Suárez-Calvet, Marc; Lladó, Albert; Barrera-Ocampo, Alvaro A; Sepulveda-Falla, Diego; Blesa, Rafael; Molinuevo, José L; Clarimón, Jordi; Ferrer, Isidre; Gelpi, Ellen; Lleó, Alberto.
In: ACTA NEUROPATHOL, Vol. 125, No. 2, 2, 2013, p. 201-213.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Distinct patterns of APP processing in the CNS in autosomal-dominant and sporadic Alzheimer disease.
AU - Pera, Marta
AU - Alcolea, Daniel
AU - Sánchez-Valle, Raquel
AU - Guardia-Laguarta, Cristina
AU - Colom-Cadena, Martí
AU - Badiola, Nahuai
AU - Suárez-Calvet, Marc
AU - Lladó, Albert
AU - Barrera-Ocampo, Alvaro A
AU - Sepulveda-Falla, Diego
AU - Blesa, Rafael
AU - Molinuevo, José L
AU - Clarimón, Jordi
AU - Ferrer, Isidre
AU - Gelpi, Ellen
AU - Lleó, Alberto
PY - 2013
Y1 - 2013
N2 - Autosomal-dominant Alzheimer disease (ADAD) is a genetic disorder caused by mutations in Amyloid Precursor Protein (APP) or Presenilin (PSEN) genes. Studies from families with ADAD have been critical to support the amyloid cascade hypothesis of Alzheimer disease (AD), the basis for the current development of amyloid-based disease-modifying therapies in sporadic AD (SAD). However, whether the pathological changes in APP processing in the CNS in ADAD are similar to those observed in SAD remains unclear. In this study, we measured ?-site APP-cleaving enzyme (BACE) protein levels and activity, APP and APP C-terminal fragments in brain samples from subjects with ADAD carrying APP or PSEN1 mutations (n = 18), patients with SAD (n = 27) and age-matched controls (n = 22). We also measured sAPP? and BACE protein levels, as well as BACE activity, in CSF from individuals carrying PSEN1 mutations (10 mutation carriers and 7 non-carrier controls), patients with SAD (n = 32) and age-matched controls (n = 11). We found that in the brain, the pattern in ADAD was characterized by an increase in APP ?-C-terminal fragment (?-CTF) levels despite no changes in BACE protein levels or activity. In contrast, the pattern in SAD in the brain was mainly characterized by an increase in BACE levels and activity, with less APP ?-CTF accumulation than ADAD. In the CSF, no differences were found between groups in BACE activity or expression or sAPP? levels. Taken together, these data suggest that the physiopathological events underlying the chronic A? production/clearance imbalance in SAD and ADAD are different. These differences should be considered in the design of intervention trials in AD.
AB - Autosomal-dominant Alzheimer disease (ADAD) is a genetic disorder caused by mutations in Amyloid Precursor Protein (APP) or Presenilin (PSEN) genes. Studies from families with ADAD have been critical to support the amyloid cascade hypothesis of Alzheimer disease (AD), the basis for the current development of amyloid-based disease-modifying therapies in sporadic AD (SAD). However, whether the pathological changes in APP processing in the CNS in ADAD are similar to those observed in SAD remains unclear. In this study, we measured ?-site APP-cleaving enzyme (BACE) protein levels and activity, APP and APP C-terminal fragments in brain samples from subjects with ADAD carrying APP or PSEN1 mutations (n = 18), patients with SAD (n = 27) and age-matched controls (n = 22). We also measured sAPP? and BACE protein levels, as well as BACE activity, in CSF from individuals carrying PSEN1 mutations (10 mutation carriers and 7 non-carrier controls), patients with SAD (n = 32) and age-matched controls (n = 11). We found that in the brain, the pattern in ADAD was characterized by an increase in APP ?-C-terminal fragment (?-CTF) levels despite no changes in BACE protein levels or activity. In contrast, the pattern in SAD in the brain was mainly characterized by an increase in BACE levels and activity, with less APP ?-CTF accumulation than ADAD. In the CSF, no differences were found between groups in BACE activity or expression or sAPP? levels. Taken together, these data suggest that the physiopathological events underlying the chronic A? production/clearance imbalance in SAD and ADAD are different. These differences should be considered in the design of intervention trials in AD.
KW - Adult
KW - Humans
KW - Male
KW - Aged
KW - Female
KW - Middle Aged
KW - Immunohistochemistry
KW - Heterozygote
KW - Blotting, Western
KW - Mutation/genetics
KW - Alzheimer Disease/cerebrospinal fluid/genetics/metabolism
KW - Amyloid Precursor Protein Secretases/cerebrospinal fluid/metabolism
KW - Amyloid beta-Protein Precursor/cerebrospinal fluid/metabolism
KW - Apolipoproteins E/genetics/metabolism
KW - Aspartic Acid Endopeptidases/cerebrospinal fluid/metabolism
KW - Central Nervous System/metabolism
KW - Neurites/pathology
KW - Presenilin-1/cerebrospinal fluid/genetics
KW - Adult
KW - Humans
KW - Male
KW - Aged
KW - Female
KW - Middle Aged
KW - Immunohistochemistry
KW - Heterozygote
KW - Blotting, Western
KW - Mutation/genetics
KW - Alzheimer Disease/cerebrospinal fluid/genetics/metabolism
KW - Amyloid Precursor Protein Secretases/cerebrospinal fluid/metabolism
KW - Amyloid beta-Protein Precursor/cerebrospinal fluid/metabolism
KW - Apolipoproteins E/genetics/metabolism
KW - Aspartic Acid Endopeptidases/cerebrospinal fluid/metabolism
KW - Central Nervous System/metabolism
KW - Neurites/pathology
KW - Presenilin-1/cerebrospinal fluid/genetics
M3 - SCORING: Journal article
VL - 125
SP - 201
EP - 213
JO - ACTA NEUROPATHOL
JF - ACTA NEUROPATHOL
SN - 0001-6322
IS - 2
M1 - 2
ER -