BACE2 beyond β-processing of APP, its neuroprotective role in cerebrovascular endothelium.

Publisher: Wiley on behalf of the International Society for Neurochemistry Country of Publication: England NLM ID: 2985190R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1471-4159 (Electronic) Linking ISSN: 00223042 NLM ISO Abbreviation: J Neurochem Subsets: MEDLINE

Publication: 2001- : Oxford, UK : Wiley on behalf of the International Society for Neurochemistry
Original Publication: New York : Raven Press

Amyloid Precursor Protein Secretases* ; Alzheimer Disease*; Humans ; Amyloid beta-Protein Precursor ; Endothelial Cells ; Aspartic Acid Endopeptidases ; Endothelium

Several proteases are involved in the proteolytic processing of the amyloid precursor protein (APP) generating the amyloidogenic Aβ peptide, which can act as the triggering pathological effector of Alzheimer's disease (AD). Among these proteases, the β-site amyloid precursor protein cleaving enzyme 2 (BACE2) is of particular interest because it was first proposed as an alternative β-secretase to its homolog BACE1; however, accumulating evidence suggests that BACE2 acts as a non-amyloidogenic α-secretase and exerts neuroprotective effects. In this issue of J Neurochem, Katusic et al. present an interesting article reporting that BACE2 plays a role in preservation of cerebral vascular endothelial nitric oxide synthase (eNOS) function, thus exerting protective functions. Their data support that the process is mediated by the large soluble non-amyloidogenic APP fragment sAPPα through the γ-aminobutyric acid type B receptor 1, which enhances the expression of a major transcription factor for eNOS gene expression in endothelial cells, the Krüppel-like factor 2. These protective functions of BACE2 contrast with the pathogenic role of BACE1 as a key player in the AD amyloidogenic pathway. Indeed, many efforts have been invested in BACE1 inhibitors as potential disease modifiers for AD. Unfortunately, the results in clinical trials have been disappointing. In this scenario, a better understanding of the functions of BACE2, as well as the selectivity of BACE1 inhibitors with respect to other β-secretases (mainly BACE2), is crucial for the development of new therapeutic agents. Furthermore, specific cellular targeting should also be considered to improve such therapies due to the diverse balance of secretases targeting APP and the complex cross-talk between them and the generated APP fragments.
(© 2023 International Society for Neurochemistry.)

Comment on: J Neurochem. 2023 Sep;166(6):928-942. (PMID: 37547981)

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Keywords: Alzheimer's disease; BACE2; brain endothelial cells; eNOS; sAPPα; vasoprotection

EC 3.4.- (Amyloid Precursor Protein Secretases)
0 (Amyloid beta-Protein Precursor)
EC 3.4.23.- (Aspartic Acid Endopeptidases)
EC 3.4.23.45 (BACE2 protein, human)

Date Created: 20230817 Date Completed: 20230918 Latest Revision: 20231004

20231215

10.1111/jnc.15940

37587672