BACE2: A Promising Neuroprotective Candidate for Alzheimer’s Disease

Yeap, Yee Jie; Kandiah, Nagaendran; Nižetić, Dean; Lim, Kah‐Leong

doi:10.3233/jad-220867

Cited by 7 publications

(3 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the model of diet-induced obesity, BACE2 knockout mice leads to exacerbated body weight gain, hyperinsulinemia, and insulin resistance. 29 In addition, BACE2 cleaves the A β protein precursor within the A β domain that accordingly prevents the generation of A β 42 peptides associated with aggregation of the A β , 30 and BACE2 loss-of-function mutation (BACE2 G446R ) showed greater apoptosis and increased levels of A β oligomers in human pluripotent stem cell–derived brain organoids. 31 Further investigation is required to confirm the relevance of BACE2 inhibitor in the treatment of diabetes and obesity.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Amino Acids Influx into Proximal Tubular Cells Improves Lysosome Function in Diabetes

Kano,

Yamaguchi,

Mise

et al. 2023

Kidney360

View full text Add to dashboard Cite

Background: Inhibition of glucose influx into proximal tubular cells (PTCs) by sodium-glucose co-transporter 2 (SGLT2) inhibitors revealed prominent therapeutic impacts on diabetic kidney disease (DKD). Collectrin (CLTRN) serves as a chaperone for the trafficking of neutral amino acid transporters in the apical membranes of proximal tubular cells. We investigated the beneficial effects of reduced influx of amino acids into proximal tubular cells in diabetes and obesity model of Cltrn-/y mice. Methods: Cltrn+/y and Cltrn-/y mice at 5 weeks of age were assigned to standard diet- (STD) and streptozotocin and high fat diet-treated (STZ-HFD) groups. Results: At 22-23 weeks of age, body weight and HbA1c levels significantly increased in STZ-HFD-Cltrn+/y compared to STD-Cltrn+/y; however, they were not altered in STZ-HFD-Cltrn-/y compared to STZ-HFD-Cltrn+/y. At 20 weeks of age, urinary albumin creatinine ratio (UACR) was significantly reduced in STZ-HFD-Cltrn-/y compared to STZ-HFD-Cltrn+/y. Under the treatments with STZ and HFD, the Cltrn gene deficiency caused significant increase in urinary concentration of amino acids such as Gln, His, Gly, Thr, Tyr, Val, Trp, Phe, Ile, Leu and Pro. In proximal tubular cells in STZ-HFD-Cltrn+/y, the enlarged lysosomes with diameter of 10 μm or more were associated with reduced autolysosomes, and the formation of giant lysosomes was prominently suppressed in STZ-HFD-Cltrn-/y. Phospho-mTOR and inactive form of phospho-TFEB were reduced in STZ-HFD-Cltrn-/y compared to STZ-HFD-Cltrn+/y. Conclusions: The reduction of amino acids influx into proximal tubular cells inactivated mTOR, activated TFEB, improved lysosome function, and ameliorated vacuolar formation of PTCs in STZ-HFD-Cltrn-/y mice.

show abstract

Section: Discussionmentioning

confidence: 99%

Inhibition of Amino Acids Influx into Proximal Tubular Cells Improves Lysosome Function in Diabetes

Kano,

Yamaguchi,

Mise

et al. 2023

Kidney360

View full text Add to dashboard Cite

show abstract

“…In this section, Li et al [19] provide new ideas on acupuncture therapy for dementia and give insights on an integrated analysis of novel therapeutic mechanisms. Additionally, Yeap and colleagues [20] give new insight into BACE2 as a promising neuroprotective target for AD in targeting novel biosimilars. Chen et al [21] examine the novel role of neural stem cells in the possible treatment of AD and highlight prospects for stem cell therapy.…”

Section: Theme 2: Novel Therapeutic Approaches Other Than Chemical Mo...mentioning

confidence: 99%

Introduction to The Special Issue: Novel Molecular Pathways and Therapeutic Challenges in Neurodegenerative Diseases

Rao

Hegde

2023

JAD

View full text Add to dashboard Cite

Neurodegenerative disorders, such as Alzheimer's disease, (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), present complex etiologies and pathologies. The lack of early detection is due to the absence of precise biomarkers [1][2][3]. The clinical management of these brain disorders has become more complex and challenging because the absence of precise novel biochemical drug targets has hindered discovery of new drugs [4][5][6]. One of the key issues is the increased incidence of neurodegenerative disorders in the world population, primarily due to an increase in life expectancy [4]. Despite an enormous upsurge in our understanding of the cellular and molecular pathways associated with cell death, the key molecular determinants to modulate these processes in human diseases is still not revealed, hindering the development of effective treatments and prevention avenues for aging and neurodegener-

show abstract

“…However, BACE2 appears to play different roles to BACE1 (Walter, 2013), and, relevantly, the physiological role of BACE2 in the proteolytic processing of APP is controversial since it can also act as an alternative α-secretase, cleaving APP within the Aβ domain region (Yan et al, 2001). This α-secretase-like activity of BACE2 can mediate neuroprotective effects in AD (Yeap et al, 2022).…”

mentioning

confidence: 99%

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

Sáez‐Valero,

Pérez‐González

2023

Journal of Neurochemistry

View full text Add to dashboard Cite

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.image

show abstract

BACE2: A Promising Neuroprotective Candidate for Alzheimer’s Disease

Cited by 7 publications

References 87 publications

Inhibition of Amino Acids Influx into Proximal Tubular Cells Improves Lysosome Function in Diabetes

Inhibition of Amino Acids Influx into Proximal Tubular Cells Improves Lysosome Function in Diabetes

Introduction to The Special Issue: Novel Molecular Pathways and Therapeutic Challenges in Neurodegenerative Diseases

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

Contact Info

Product

Resources

About