TY - JOUR
T1 - BACE2 expression increases in human neurodegenerative disease
AU - Holler, Christopher J.
AU - Webb, Robin L.
AU - Laux, Ashley L.
AU - Beckett, Tina L.
AU - Niedowicz, Dana M.
AU - Ahmed, Rachel R.
AU - Liu, Yinxing
AU - Simmons, Christopher R.
AU - Dowling, Amy L.S.
AU - Spinelli, Angela
AU - Khurgel, Moshe
AU - Estus, Steven
AU - Head, Elizabeth
AU - Hersh, Louis B.
AU - Murphy, M. Paul
PY - 2012/1
Y1 - 2012/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajpath.2011.09.034
DO - 10.1016/j.ajpath.2011.09.034
M3 - Article
C2 - 22074738
AN - SCOPUS:83455164148
SN - 0002-9440
VL - 180
SP - 337
EP - 350
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 1
ER -