title: BACE2 expression increases in human neurodegenerative disease.
abstract: β-Secretase, the rate-limiting enzymatic activity in the production of the amyloid-β (Aβ) peptide, is a major target of Alzheimer's disease (AD) therapeutics. There are two forms of the enzyme: β-site Aβ precursor protein cleaving enzyme (BACE) 1 and BACE2. Although BACE1 increases in late-stage AD, little is known about BACE2. We conducted a detailed examination of BACE2 in patients with preclinical to late-stage AD, including amnestic mild cognitive impairment, and age-matched controls, cases of frontotemporal dementia, and Down's syndrome. BACE2 protein and enzymatic activity increased as early as preclinical AD and were found in neurons and astrocytes. Although the levels of total BACE2 mRNA were unchanged, the mRNA for BACE2 splice form C (missing exon 7) increased in parallel with BACE2 protein and activity. BACE1 and BACE2 were strongly correlated with each other at all levels, suggesting that their regulatory mechanisms may be largely shared. BACE2 was also elevated in frontotemporal dementia but not in Down's syndrome, even in patients with substantial Aβ deposition. Thus, expression of both forms of β-secretase are linked and may play a combined role in human neurologic disease. A better understanding of the normal functions of BACE1 and BACE2, and how these change in different disease states, is essential for the future development of AD therapeutics.
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536-0230, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Holler
authors.forename: Robin L
authors.initials: RL
authors.lastname: Webb
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Laux
authors.forename: Tina L
authors.initials: TL
authors.lastname: Beckett
authors.forename: Dana M
authors.initials: DM
authors.lastname: Niedowicz
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Ahmed
authors.forename: Yinxing
authors.initials: Y
authors.lastname: Liu
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Simmons
authors.forename: Amy L S
authors.initials: AL
authors.lastname: Dowling
authors.forename: Angela
authors.initials: A
authors.lastname: Spinelli
authors.forename: Moshe
authors.initials: M
authors.lastname: Khurgel
authors.forename: Steven
authors.initials: S
authors.lastname: Estus
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Head
authors.forename: Louis B
authors.initials: LB
authors.lastname: Hersh
authors.forename: M Paul
authors.initials: MP
authors.lastname: Murphy
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001923:Brain Chemistry; D005260:Female; D006801:Humans; D008297:Male; D015260:Neprilysin / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human; D015260:Neprilysin
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