Mechanisms of amyloid-β34 generation indicate a pivotal role for BACE1 in amyloid homeostasis

被引：9

作者：

Ulku, Irem ^{[1
]}

Liebsch, Filip ^{[1
,2
]}

Akerman, S. Can ^{[3
]}

Schulz, Jana F. ^{[4
]}

Kulic, Luka ^{[5
]}

Hock, Christoph ^{[6
,7
]}

Pietrzik, Claus ^{[8
]}

Di Spiezio, Alessandro ^{[9
]}

Thinakaran, Gopal ^{[10
,11
]}

Saftig, Paul ^{[9
]}

Multhaup, Gerhard ^{[1
,3
]}

机构：

[1] McGill Univ, Integrated Program Neurosci, Montreal, PQ H3G0B1, Canada

[2] Univ Cologne, Inst Biochem, Dept Chem, D-50674 Cologne, Germany

[3] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ H3G1Y6, Canada

[4] Free Univ Berlin, Inst Chemie & Biochemie, D-14195 Berlin, Germany

[5] F Hoffmann La Roche Ltd, Roche Pharm Res & Early Dev, CH-4070 Basel, Switzerland

[6] Univ Zurich, Inst Regenerat Med, CH-8952 Schlieren, Switzerland

[7] Neurimmune AG, CH-8952 Schlieren, Switzerland

[8] Johannes Gutenberg Univ Mainz, Univ Med Ctr Johannes Gutenberg, Inst Pathobiochemistry, Dept Mol Neurodegenerat, Duesbergweg 6, D-55099 Mainz, Germany

[9] CAU Kiel, Biochem Inst, Olshausenstr 40, D-24098 Kiel, Germany

[10] Univ S Florida, Dept Mol Med, Tampa, FL 33613 USA

[11] Univ S Florida, Byrd Alzheimers Inst, Tampa, FL 33613 USA

来源：

SCIENTIFIC REPORTS | 2023年 / 13卷 / 01期

基金：

英国医学研究理事会; 加拿大自然科学与工程研究理事会; 美国国家卫生研究院; 加拿大健康研究院;

关键词：

BETA-SECRETASE ACTIVITY; PRECURSOR PROTEIN; A-BETA; ALZHEIMERS-DISEASE; TRANSGENIC MICE; PEPTIDE; IDENTIFICATION; DEPOSITION; EXPRESSION; APP;

D O I：

10.1038/s41598-023-28846-z

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The beta-site amyloid precursor protein (APP) cleaving enzyme (BACE1) was discovered due to its "amyloidogenic" activity which contributes to the production of amyloid-beta (A beta) peptides. However, BACE1 also possesses an "amyloidolytic" activity, whereby it degrades longer A beta peptides into a non-toxic A beta 34 intermediate. Here, we examine conditions that shift the equilibrium between BACE1 amyloidogenic and amyloidolytic activities by altering BACE1/APP ratios. In Alzheimer disease brain tissue, we found an association between elevated levels of BACE1 and A beta 34. In mice, the deletion of one BACE1 gene copy reduced BACE1 amyloidolytic activity by similar to 50%. In cells, a stepwise increase of BACE1 but not APP expression promoted amyloidolytic cleavage resulting in dose-dependently increased A beta 34 levels. At the cellular level, a mislocalization of surplus BACE1 caused a reduction in A beta 34 levels. To align the role of gamma-secretase in this pathway, we silenced Presenilin (PS) expression and identified PS2-gamma-secretase as the main gamma-secretase that generates A beta 40 and A beta 42 peptides serving as substrates for BACE1's amyloidolytic cleavage to generate A beta 34.

引用

页数：15

共 66 条

[1] Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer's disease [J].