BACE1 and BACE2 in pathologic and normal human muscle.
BACE1 and BACE2 are recently discovered enzymes participating in processing of amyloid beta precursor protein (AbetaPP). Their discovery is contributing importantly to understanding the mechanism of amyloid-beta generation, and hence the pathogenesis of Alzheimer's disease (AD). Sporadic inclusion-body myositis (s-IBM) and hereditary inclusion-body myopathy (h-IBM) are progressive muscle diseases in which overproduction of AbetaPP and accumulation of its presumably toxic proteolytic product amyloid-beta (Abeta) in abnormal muscle fibers appear to play an important upstream role in the pathogenic cascade. In normal human muscle AbetaPP was also shown to be present and presumably playing a role (a) at neuromuscular junctions and (b) during muscle development. To investigate whether BACE1 and BACE2 play a role in normal and diseased human muscle, we have now studied them by immunocytochemistry and immunoblotting in 35 human muscle biopsies, including: 5 s-IBM; 5 chromosome-9p1-linked quadriceps-sparing h-IBM; and 25 control muscle biopsies. In addition, expression of BACE1 and BACE2 was studied in normal cultured human muscle. Our studies demonstrate that BACE1 and BACE2 (a) are expressed in normal adult muscle at the postsynaptic domain of neuromuscular junctions, and in cultured human muscle; (b) are accumulated in the form of plaque-like inclusions in both s-IBM and h-IBM vacuolated muscle fibers; and (c) are immunoreactive in necrotizing muscle fibers. Accordingly, BACE1 and BACE2 participate in normal and abnormal processes of human muscle, suggesting that their functions are broader than previously thought.
Vattemi
Gaetano
G
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles 90017-1912, USA.
Engel
W King
WK
McFerrin
Janis
J
Pastorino
Lucia
L
Buxbaum
Joseph D
JD
Askanas
Valerie
V
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis*; D001706:Biopsy; D002478:Cells, Cultured; D010450:Endopeptidases; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000473:pathology; D009220:Myositis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018979:Myositis, Inclusion Body / Q000201:enzymology* / Q000473:pathology
D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human