BACE1 and BACE2 in pathologic and normal human muscle

• Published in: Experimental neurology Vol. 179; no. 2; pp. 150 - 158
• Main Authors: Vattemi, Gaetano, Engel, W.King, McFerrin, Janis, Pastorino, Lucia, Buxbaum, Joseph D, Askanas, Valerie
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.02.2003; Elsevier
• Subjects: Amyloid Precursor Protein Secretases; Amyloid-β; Aspartic Acid Endopeptidases - biosynthesis; BACE1; BACE2; Biological and medical sciences; Biopsy; Cells, Cultured; Cultured human muscle fibers; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Diseases of striated muscles. Neuromuscular diseases; Endopeptidases; Hereditary inclusion-body myopathy; Humans; Immunoblotting; Immunohistochemistry; Medical sciences; Muscle Fibers, Skeletal - enzymology; Muscle Fibers, Skeletal - pathology; Muscle Fibers, Skeletal - ultrastructure; Muscle, Skeletal - enzymology; Muscle, Skeletal - pathology; Myopathy; Myositis - enzymology; Myositis - genetics; Myositis - pathology; Myositis, Inclusion Body - enzymology; Myositis, Inclusion Body - pathology; Neurology; Neuromuscular junctions; Sporadic inclusion-body myositis; BACE1; Cultured human muscle fibers; BACE2; Sporadic inclusion-body myositis; Hereditary inclusion-body myopathy; Neuromuscular junctions; Amyloid-β; Myopathy; Sporadic; Alzheimer disease; Immunocytochemistry; Pathogenesis; Neuromuscular junction; Degenerative disease; Amyloid; Inclusion body; Human; Nervous system diseases; Amyloid precursor protein; Cerebral disorder; Striated muscle disease; Biopsy; β Amyloid protein; Central nervous system disease; Myositis
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/S0014-4886(02)00025-0

BACE1 and BACE2 are recently discovered enzymes participating in processing of amyloid β precursor protein (AβPP). Their discovery is contributing importantly to understanding the mechanism of amyloid-β 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 AβPP and accumulation of its presumably toxic proteolytic product amyloid-β (Aβ) in abnormal muscle fibers appear to play an important upstream role in the pathogenic cascade. In normal human muscle AβPP 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.