Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibition Impairs Synaptic Plasticity via Seizure Protein 6

Zhu, Kaichuan; Xiang, Xianyuan; Filser, Severin; Marinković, Petar; Dorostkar, Mario M.; Crux, Sophie; Neumann, Ulf; Shimshek, Derya R.; Rammes, Gerhard; Haass, Christian; Lichtenthaler, Stefan F.; Gunnersen, Jenny M.; Herms, Jochen

doi:10.1016/j.biopsych.2016.12.023

Cited by 91 publications

(101 citation statements)

References 62 publications

(97 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although associated with β‐cleavage of APP, leading to greater Aβ and βCTF expression, attenuation of Bace1 levels by MCS may indicate a counterintuitive normalization of APP processing in vulnerable neurons that reflects the importance of steady‐state Aβ and βCTF levels, underscoring the importance of evaluating βCTF expression in DS/AD models (Jiang et al, ). Alternatively, Bace1 deficiency may be considered detrimental, as a loss of Bace1 expression impairs myelination (Hu, Hu, Dai, Trapp, & Yan, ) and causes hippocampal synaptic deficits (Petrus & Lee, ; Wang et al, ; Zhu et al, ), illustrating the need for normative Bace1 levels. MCS also restores the normal expression of two truncated forms of tau ( Mapt2N6D and Mapt2N6P ).…”

Section: Discussionmentioning

confidence: 99%

CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation

et al. 2018

View full text Add to dashboard Cite

Although there are changes in gene expression and alterations in neuronal density and afferent inputs in the forebrain of trisomic mouse models of Down syndrome (DS) and Alzheimer's disease (AD), there is a lack of systematic assessments of gene expression and encoded proteins within individual vulnerable cell populations, precluding translational investigations at the molecular and cellular level. Further, no effective treatment exists to combat intellectual disability and basal forebrain cholinergic neurodegeneration seen in DS. To further our understanding of gene expression changes before and following cholinergic degeneration in a well-established mouse model of DS/AD, the Ts65Dn mouse, we assessed RNA expression levels from CA1 pyramidal neurons at two adult ages (∼6 months of age and ∼11 months of age) in both Ts65Dn and their normal disomic (2N) littermates. We further examined a therapeutic intervention, maternal choline supplementation (MCS), which has been previously shown to lessen dysfunction in spatial cognition and attention, and have protective effects on the survival of basal forebrain cholinergic neurons in the Ts65Dn mouse model. Results indicate that MCS normalized expression of several genes in key gene ontology categories, including synaptic plasticity, calcium signaling, and AD-associated neurodegeneration related to amyloid-beta peptide (Aβ) clearance. Specifically, normalized expression levels were found for endothelin converting enzyme-2 (Ece2), insulin degrading enzyme (Ide), Dyrk1a, and calcium/calmodulin-dependent protein kinase II (Camk2a), among other relevant genes. Single population expression profiling of vulnerable CA1 pyramidal neurons indicates that MCS is a viable therapeutic for long-term reprogramming of key transcripts involved in neuronal signaling that are dysregulated in the trisomic mouse brain which have translational potential for DS and AD.

show abstract

Section: Discussionmentioning

confidence: 99%

CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Therefore, Zhu et al tried in their work to explore whether BACE1 inhibition is causing synaptic dysfunction due to perturbation in SEZ6 function. Thus, it was demonstrated that prolonged BACE1 inhibition using potent inhibitor like NB‐360 was only causing reversible spinal density reduction in wild type mice (control) while such effect was not seen in SEZ6 knockout mice group . Moreover, synaptic impairment caused by BACE1 inhibition was prevented by knocking out SEZ6 from matured neurons .…”

Section: Failure Of Bace1 Inhibitors: Lessons To the Futurementioning

confidence: 99%

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

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

208

175

View full text Add to dashboard Cite

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.

show abstract

“…On the other hand, though, the levels of the substrate candidate NLGN2 would be expected to be increased as well and may sequester the increased MDGA1 levels, thus not resulting in a change in inhibitory synapse formation. Yet, other BACE1 substrates, such as SEZ6, voltage‐gated sodium channels, Jagged, and Nrg1, also affect directly or indirectly synaptic transmission . Thus, synaptic alterations in BACE1‐deficent mice may not be attributed easily to individual substrates, but may reflect complex changes in the function of multiple substrates.…”

Section: Discussionmentioning

confidence: 99%

“…Yet, other BACE1 substrates, such as SEZ6, voltage-gated sodium channels, Jagged, and Nrg1, also affect directly or indirectly synaptic transmission. [25][26][27][28]32,78,79 Thus, synaptic alterations in BACE1-deficent mice may not be attributed easily to individual substrates, but may reflect complex changes in the function of multiple substrates.…”

Section: Discussionmentioning

confidence: 99%

Mouse brain proteomics establishes MDGA1 and CACHD1 as in vivo substrates of the Alzheimer protease BACE1

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibition Impairs Synaptic Plasticity via Seizure Protein 6

Abstract: Our results suggest that SEZ6 plays an important role in maintaining normal dendritic spine dynamics. Furthermore, SEZ6 is involved in BACE1 inhibition-induced structural and functional synaptic alterations.

Cited by 91 publications

References 62 publications

CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation

CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation

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

Mouse brain proteomics establishes MDGA1 and CACHD1 as in vivo substrates of the Alzheimer protease BACE1

Contact Info

Product

Resources

About