Abstract:
:Amyloid beta (Aβ) is a major pathological marker in Alzheimer's disease (AD), which is principally regulated by the rate-limiting β-secretase (i.e., BACE1) cleavage of amyloid precursor protein (APP). However, how BACE1 activity is posttranslationally regulated remains incompletely understood. Here, we show that BACE1 is predominantly SUMOylated at K501 residue, which escalates its protease activity and stability and subsequently increases Aβ production, leading to cognitive defect seen in the AD mouse model. Compared with a non-SUMOylated K501R mutant, injection of wild-type BACE1 significantly increases Aβ production and triggers cognitive dysfunction. Furthermore, overexpression of wild-type BACE1, but not non-SUMOylated K501R mutant, facilitates senile plaque formation and aggravates the cognitive deficit seen in the APP/PS1 AD mouse model. Together, our data strongly suggest that K501 SUMOylation on BACE1 plays a critical role in mediating its stability and enzymatic activity.
journal_name
Proc Natl Acad Sci U S Aauthors
Bao J,Qin M,Mahaman YAR,Zhang B,Huang F,Zeng K,Xia Y,Ke D,Wang Q,Liu R,Wang JZ,Ye K,Wang Xdoi
10.1073/pnas.1800498115subject
Has Abstractpub_date
2018-04-10 00:00:00pages
3954-3959issue
15eissn
0027-8424issn
1091-6490pii
1800498115journal_volume
115pub_type
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