Role of BACE1 in Alzheimer’s synaptic function

Das, Brati; Yan, Riqiang

doi:10.1186/s40035-017-0093-5

Cited by 102 publications

(67 citation statements)

References 105 publications

(105 reference statements)

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“…BACE, also known as beta-site amyloid precursor protein cleaving enzyme, has been implicated in the formation of the Aβ42 peptide found within amyloid plaques [37]. BACE inhibition is known to prevent the production of Aβ in animals and may be a potential therapeutic approach for the treatment of patients with AD [38].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Effects of Human Amniotic Epithelial Stem Cells in a Transgenic Mouse Model of Alzheimer’s Disease

Kim

Suh

Chang

2020

IJMS

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Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is characterized clinically by cognitive decline and pathologically by the development of amyloid plaques. AD is the most common cause of dementia among older people. However, there is currently no cure for AD. In this study, we aimed to elucidate the therapeutic effects of human amniotic epithelial stem cells (hAESCs) in a transgenic mouse model of AD. Tg2576 transgenic (Tg) mice underwent behavioral tests, namely the Morris water maze and Y-maze tests, to assess their cognitive function. In the Morris water maze test, hAESC-treated Tg mice exhibited significantly shorter escape latencies than vehicle-treated Tg mice. In the Y-maze test, hAESC-treated Tg mice exhibited significantly higher rate of spontaneous alteration than vehicle-treated Tg mice, while the total number of arm entries did not differ between the groups. Furthermore, Congo red staining revealed that hAESCs injection reduced the number of amyloid plaques present in the brains of Tg mice. Finally, beta-secretase (BACE) activity was significantly decreased in Tg mice at 60 min after hAESCs injection. In this study, we found that intracerebral injection of hAESCs alleviated cognitive impairment in a Tg2576 mouse model of AD. Our results indicate that hAESCs injection reduced amyloid plaques caused by reduced BACE activity. These results indicate that hAESCs may be a useful therapeutic agent for the treatment of AD-related memory impairment.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Effects of Human Amniotic Epithelial Stem Cells in a Transgenic Mouse Model of Alzheimer’s Disease

Kim

Suh

Chang

2020

IJMS

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“…32 Moreover, many in vivo studies confirmed that β-secretase play a vital role in AD progression and the use of BACE1 inhibitors improved the neurological function and surpassed the neurological defects imposed in mice of AD model. 33 For example, in a recent study utilizing NB-360 as BACE1 inhibitor in mice with familial Alzheimer disease, the administration of this agent resulted in the enhancement of neuronal activity and the improvement of memory. 34 These effects were attributed to the ability of NB-360 to reduce the formation of Aβ oligomers.…”

Section: Alzheimer's Disease Pathology and Targetsmentioning

confidence: 99%

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

230

175

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Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches of AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1), which is involved in the rate‐limiting step of the cleavage process of the amyloid precursor protein (APP) leading to the generation of the neurotoxic amyloid β (Aβ) protein after the γ‐secretase completes its function. The produced insoluble Aβ aggregates lead to plaques deposition and neurodegeneration. BACE1 is, therefore, one of the attractive targets for the treatment of AD. This approach led to the development of potent BACE1 inhibitors, many of which were advanced to late stages in clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new targets to uncover the mystery behind AD. In this review, we aim to discuss the most promising classes of BACE1 inhibitors with a description and analysis of their pharmacodynamic and pharmacokinetic parameters, with more focus on the lead drug candidates that reached late stages of clinical trials, such as MK8931, AZD‐3293, JNJ‐54861911, E2609, and CNP520. In addition, the manuscript discusses the safety concerns and insignificant physiological effects, which were highlighted for the most successful BACE1 inhibitors. Furthermore, the review demonstrates with increasing evidence that despite tremendous efforts and promising results conceived with BACE1 inhibitors, the latest studies suggest that their clinical use for treating Alzheimer's disease should be reconsidered. Finally, the review sheds light on alternative therapeutic options for targeting AD.

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“…BACE1 is an extensively studied target, due to its potential role in Alzheimer's disease [61]. Indeed, over 300 BACE1 crystal structures were present in the PDB at the time of this challenge.…”

Section: Overview Of Pose Prediction Accuracymentioning

confidence: 99%

D3R grand challenge 4: blind prediction of protein–ligand poses, affinity rankings, and relative binding free energies

parks

Gaieb

Chiu

et al. 2020

J Comput Aided Mol Des

102

101

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The Drug Design Data Resource (D3R) aims to identify best practice methods for computer aided drug design through blinded ligand pose prediction and affinity challenges. Herein, we report on the results of Grand Challenge 4 (GC4). GC4 focused on proteins beta secretase 1 and Cathepsin S, and was run in an analogous manner to prior challenges. In Stage 1, participant ability to predict the pose and affinity of BACE1 ligands were assessed. Following the completion of Stage 1, all BACE1 co-crystal structures were released, and Stage 2 tested affinity rankings with co-crystal structures. We provide an analysis of the results and discuss insights into determined best practice methods.

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Role of BACE1 in Alzheimer’s synaptic function

Cited by 102 publications

References 105 publications

Therapeutic Effects of Human Amniotic Epithelial Stem Cells in a Transgenic Mouse Model of Alzheimer’s Disease

Therapeutic Effects of Human Amniotic Epithelial Stem Cells in a Transgenic Mouse Model of Alzheimer’s Disease

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

D3R grand challenge 4: blind prediction of protein–ligand poses, affinity rankings, and relative binding free energies

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