β-Secretase Processing in the Trans-Golgi Network Preferentially Generates Truncated Amyloid Species That Accumulate in Alzheimer’s Disease Brain

Huse, Jason T.; Liu, Kangning; Pijak, Donald S.; Carlin, Dan; Lee, Virginia M.-Y.; Doms, Robert W.

doi:10.1074/jbc.m111141200

Cited by 176

The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.

β-Secretase Processing in the Trans-Golgi Network Preferentially Generates Truncated Amyloid Species That Accumulate in Alzheimer’s Disease Brain

Huse, Jason T., Liu, Kangning, Pijak, Donald S., Carlin, Dan, Lee, Virginia M.-Y., Doms, Robert W.·2002·Journal of Biological Chemistry

DOI 10.1074/jbc.m111141200

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Abstract

The amyloid beta (A beta) peptide that accumulates in Alzheimer's disease brain is derived from the proteolytic processing of the amyloid precursor protein by beta- and gamma-secretase activities. The beta-secretase enzyme beta-site amyloid precursor protein-cleaving enzyme (BACE) generates the N terminus of A beta by cleavage at either Asp(1) (beta-site) or Glu(11) (beta'-site), ultimately leading to the production of full-length A beta 1-40/42 or truncated A beta 11-40/42. The functional significance of this variable cleavage site specificity as well as the relative pathological impact of full-length versus N-terminally truncated A beta remains largely unknown. In our analysis of BACE reactivity in cell culture, we found that the preference of the protease for either beta- or beta'-cleavage was strongly dependent on intracellular localization. Within the endoplasmic reticulum, beta-site proteolysis predominated, whereas in the trans-Golgi network, beta'-cleavage was favored. Furthermore, the contrasting cleavage site specificities of BACE were not simply due to differences in organelle pH or the oligosaccharide composition of the glycoproteins involved. Examination of post-mortem brain specimens revealed significant levels of A beta 11-40/42 within insoluble amyloid pools. Taken together, these data support an important role for beta'-cleavage in the process of cerebral amyloid deposition and localize the processing event to the trans-Golgi network.

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BACE-1 can catalyze amyloidolytic processing by cleavage between Tyr10 and Glu11 of the Aβ sequence, the β'-cleavage site.
“BACE-1 can also catalyze amyloidolytic processing by cleavage between Tyr10 and Glu11 of the Aβ sequence (Huse et al., 2002; Liu et al., 2002; Kimura et al., 2016), the so-called β’-cleavage site (Figure 1).”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Huse et al., 2002
A causal effect between β'-cleavage and neuroprotection is not straightforward because Aβ11-40 is found in insoluble Aβ pools of post-mortem AD brains.
“However, a causal effect between β’-cleavage and neuroprotection is not straight forward as Aβ11–40 is found in insoluble Aβ pools of post-mortem AD brains (Huse et al., 2002).”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Huse et al., 2002

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Authors: Huse, J. T., Liu, K., Pijak, D. S., Carlin, D., Lee, V. M.-Y., & Doms, R. W.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2002-05
Volume: 277
Issue: 18
Pages: 16278-16284
ISSN: 0021-9258
DOI: 10.1074/jbc.m111141200
Cited by: 176
References: 5
Language: en
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 6759 d)

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β-Secretase Processing in the Trans-Golgi Network Preferentially Generates Truncated Amyloid Species That Accumulate in Alzheimer’s Disease Brain

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