BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions

Hu, Xiangyou; Das, Brati; Hou, Hailong; He, Wanxia; Yan, Riqiang

doi:10.1084/jem.20171831

Cited by 106 publications

(108 citation statements)

References 41 publications

(49 reference statements)

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“…a phase II clinic trial and resulted in a significant slowing of clinical decline and reduction in amyloid beta accumulation in the brain; this result provides compelling evidence that further supports our use of the β-amyloid hypothesis as a basis for selecting therapeutic targets for combating AD (Hu, Das, Hou, He, & Yan, 2018;https://www.eisai.com/news/2018/ news201858.html).…”

Section: Introductionmentioning

confidence: 60%

“…The challenges associated with the β‐amyloid hypothesis have resulted in continual failures (Egan et al., ; Honig et al., ; Timmers et al., ). However, there have been some successes, such as the latest report by Eisai and Biogen, who developed an anti‐amyloid beta protofibril antibody, BAN2401, which was tested in 856 patients with early AD in a phase II clinic trial and resulted in a significant slowing of clinical decline and reduction in amyloid beta accumulation in the brain; this result provides compelling evidence that further supports our use of the β‐amyloid hypothesis as a basis for selecting therapeutic targets for combating AD (Hu, Das, Hou, He, & Yan, ; https://www.eisai.com/news/2018/news201858.html).…”

Section: Introductionmentioning

confidence: 95%

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Design, synthesis, and biological evaluation of 4‐aminopyrimidine or 4,6‐diaminopyrimidine derivatives as beta amyloid cleaving enzyme‐1 inhibitors

Lü

Wang

et al. 2019

Chem Biol Drug Des

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A series of novel aminopyrimidine and diaminopyrimidine derivatives were designed and optimized to improve their potency and permeability relative to lead compound 1 (IC50 = 37.4 μM), which was discovered in a previous virtual screening. The potency of the optimized compound, 13g (IC50 = 1.4 μM), was 26‐fold greater than that of 1 based on a fluorescence resonance energy transfer assay, and a parallel artificial membrane permeability assay suggested that it could pass through the blood‐brain barrier. Additionally, several compounds containing selenium showed good potencies and deserve further investigation as anti‐Alzheimer's agents.

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Section: Introductionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 95%

Design, synthesis, and biological evaluation of 4‐aminopyrimidine or 4,6‐diaminopyrimidine derivatives as beta amyloid cleaving enzyme‐1 inhibitors

Lü

Wang

et al. 2019

Chem Biol Drug Des

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show abstract

“…It was further assumed, therefore, that the suppression of APP proteolysis might alleviate the disease (38)(39)(40). And, indeed, inhibition of beta secretase rescued functional impairments and actually reversed the disease in animal models bioengineered to imitate familial AD (41)(42)(43)(44). However, in several large human clinical trials such inhibition was completely inefficient in sporadic AD (24).…”

Section: Ipcr: Physiologically Occurring Intracellular Polymerase Chamentioning

confidence: 99%

Protein-Encoding RNA-to-RNA Information Transfer in Mammalian Cells: Principles of RNA-Dependent mRNA Amplification

Volloch¹

2019

Preprint

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The transfer of protein-encoding genetic information from DNA to RNA to protein, a process formalized as the “Central Dogma of Molecular Biology”, has undergone a significant evolution since its inception. It was amended to account for the information flow from RNA to DNA, the reverse transcription, and for the information transfer from RNA to RNA, the RNA-dependent RNA synthesis. These processes, both potentially leading to protein production, were initially described only in viral systems, and although RNA-dependent RNA polymerase activity was shown to be present, and RNA-dependent RNA synthesis found to occur, in most, if not all, mammalian cells, its function was presumed to be restricted to regulatory. However, recent results, obtained in several systems, strongly indicate the occurrence of protein-encoding RNA to RNA information transfer in mammalian cells. It can result in the rapid production of the extraordinary quantities of specific proteins as was seen in cases of terminal cellular differentiation and during cellular deposition of extracellular matrix molecules. A malfunction of this process may be involved in pathologies associated either with the deficiency of a protein normally produced by this mechanism or with the abnormal abundance of a protein or of its C-terminal fragment. It seems to be responsible for some types of familial thalassemia and may underlie the overproduction of beta amyloid in sporadic Alzheimer’s disease. The potential physiological, therapeutic and bioengineering significance of this process appears to be substantial. The aim of the present article is to systematize the current knowledge and understanding of RNA-dependent amplification of mammalian mRNA. The outlined framework introduces unexpected features of the mRNA amplification such as its second Tier, a physiologically occurring intracellular PCR, iPCR, a “Two-Tier Paradox” and RNA “Dark Matter”. It also describes novel experimental bioengineering designs and may serve as a basis for new directions of investigations into the mechanisms underlying the mammalian mRNA amplification processes.

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“…Recently, the media headlined a report that that by reducing the level of the enzyme β-site amyloid precursor protein cleaving enzyme 1 (BACE1) through genetic modification in mice as they aged, either prevented or reversed the formation of amyloid plaques in the brain [28]. However, a few years ago, PBM produced similar results in an animal study without gaining the same level of attention.…”

Section: Evidence With Animal Modelsmentioning

confidence: 99%

The Growing Evidence for Photobiomodulation as a Promising Treatment for Alzheimer’s Disease

Lim¹

2018

JBM

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Despite the current belief that there is no effective treatment for Alzheimer's Disease (AD), one emerging modality may change this belief: Photobiomodulation (PBM). It has credible mechanisms and growing evidence to support its case. Transcranial PBM for AD is a single intervention with multiple pathway mechanisms stemming from delivering low energy near infrared (NIR) light to the mitochondria in brain cells. The mechanisms involve the activation of gene transcription that lead to neuronal recovery, removal of toxic plaques, normalizing network oscillations that can lead to improved cognition and functionality. When PBM is delivered at 810 nm wavelength and pulsed at 40 Hz, early evidence suggests that very significant outcomes are possible. Literature related to PBM and AD has covered in vitro cellular, animal and human case reports, with promising results. They warrant robust randomized trials which are either ongoing or ready to start. The evidence in human studies is manifested in assessment scales such ADAS-cog, MMSE, and ADAS-ADL, and are supported by fMRI imaging and EEG.

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BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions

Abstract: This study uses mouse models to answer how BACE1 inhibitory drugs will be beneficial to Alzheimer’s patients. Hu et al. find that sequentially increased deletion of BACE1 in one adult Alzheimer’s mouse model reverses preexisting amyloid plaques and mitigates synaptic failures.

Cited by 106 publications

References 41 publications

Design, synthesis, and biological evaluation of 4‐aminopyrimidine or 4,6‐diaminopyrimidine derivatives as beta amyloid cleaving enzyme‐1 inhibitors

Design, synthesis, and biological evaluation of 4‐aminopyrimidine or 4,6‐diaminopyrimidine derivatives as beta amyloid cleaving enzyme‐1 inhibitors

Protein-Encoding RNA-to-RNA Information Transfer in Mammalian Cells: Principles of RNA-Dependent mRNA Amplification

The Growing Evidence for Photobiomodulation as a Promising Treatment for Alzheimer’s Disease

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