Lack of β-amyloid cleaving enzyme-1 (BACE1) impairs long-term synaptic plasticity but enhances granule cell excitability and oscillatory activity in the dentate gyrus in vivo

Vnencak, Matej; Schölvinck, Marieke L.; Schwarzacher, Stephan W.; Deller, Thomas; Willem, Michael; Jedlicka, Paul

doi:10.1007/s00429-019-01836-6

Cited by 10 publications

(8 citation statements)

References 84 publications

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“…However, major clinical trials were discontinued due to a series of adverse effects or no improvement and even accelerated cognitive decline in patients (Coimbra et al, 2018;Egan et al, 2019). On the same note, mice lacking BACE1 showed increased neural excitability and spontaneous seizure activity (Hitt et al, 2010;Hu et al, 2010;Zhu et al, 2018;Vnencak et al, 2019), which have been linked to impaired homeostatic mechanisms (Wondolowski and Dickman, 2013;González et al, 2015). Although it is clear that BACE1 targets several other substrates in the nervous system (Barão et al, 2016), these observations support the notion that some of the adverse effects of clinically used BACE1 inhibitors could be explained by an impairment of Aβ-mediated homeostatic synaptic plasticity.…”

Section: Clinical Implications and Perspectivementioning

confidence: 99%

Hebbian and Homeostatic Synaptic Plasticity—Do Alterations of One Reflect Enhancement of the Other?

Galanis

Vlachos

2020

Front. Cell. Neurosci.

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During the past 50 years, the cellular and molecular mechanisms of synaptic plasticity have been studied in great detail. A plethora of signaling pathways have been identified that account for synaptic changes based on positive and negative feedback mechanisms. Yet, the biological significance of Hebbian synaptic plasticity (= positive feedback) and homeostatic synaptic plasticity (= negative feedback) remains a matter of debate. Specifically, it is unclear how these opposing forms of plasticity, which share common downstream mechanisms, operate in the same networks, neurons, and synapses. Based on the observation that rapid and input-specific homeostatic mechanisms exist, we here discuss a model that is based on signaling pathways that may adjust a balance between Hebbian and homeostatic synaptic plasticity. Hence, "alterations" in Hebbian plasticity may, in fact, resemble "enhanced" homeostasis, which rapidly returns synaptic strength to baseline. In turn, long-lasting experience-dependent synaptic changes may require attenuation of homeostatic mechanisms or the adjustment of homeostatic setpoints at the single-synapse level. In this context, we propose a role for the proteolytic processing of the amyloid precursor protein (APP) in setting a balance between the ability of neurons to express Hebbian and homeostatic synaptic plasticity.

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Section: Clinical Implications and Perspectivementioning

confidence: 99%

Hebbian and Homeostatic Synaptic Plasticity—Do Alterations of One Reflect Enhancement of the Other?

Galanis

Vlachos

2020

Front. Cell. Neurosci.

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“…Recently an in vivo study on the β-secretase BACE-1 confirmed the essential role of proteolytic peptides generated within the amyloidogenic pathway. Loss of BACE-1 resulted in increased granule cell excitability and prolonged paired-pulse-inhibition as well as altered network gamma oscillations and impaired synaptic plasticity (Vnencak and others 2019).…”

Section: App and Synaptic Plasticitymentioning

confidence: 99%

Amyloid, APP, and Electrical Activity of the Brain

et al. 2019

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The Amyloid Precursor Protein (APP) is infamous for its proposed pivotal role in the pathogenesis of Alzheimer’s disease (AD). Much research on APP focusses on potential contributions to neurodegeneration, mostly based on mouse models with altered expression or mutated forms of APP. However, cumulative evidence from recent years indicates the indispensability of APP and its metabolites for normal brain physiology. APP contributes to the regulation of synaptic transmission, plasticity, and calcium homeostasis. It plays an important role during development and it exerts neuroprotective effects. Of particular importance is the soluble secreted fragment APPsα which mediates many of its physiological actions, often counteracting the effects of the small APP-derived peptide Aβ. Understanding the contribution of APP for normal functions of the nervous system is of high importance, both from a basic science perspective and also as a basis for generating new pathophysiological concepts and therapeutic approaches in AD. In this article, we review the physiological functions of APP and its metabolites, focusing on synaptic transmission, plasticity, calcium signaling, and neuronal network activity.

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“…Thus, the ability of SNH6 to suppress Aβ production by astrocytes via decreasing BACE1 expression may reduce Aβ burden without complete ablation of BACE1 activity. This is important, when considering BACE1 as the target of a therapeutic strategy in AD, as the complete loss of BACE1 activity in BACE1‐deficient mice was associated with deleterious effects on synaptic plasticity at entorhinal‐dentate synapses (Vnencak et al, ) and on hippocampal neurogenesis (Carney, ). The authors of future preclinical trials with SNH6 will have to balance, while trying to determine the optimal therapeutic dose interval, the maximisation of the iron chelating, NAD + donating, and other advantageous effects of this compound with the need to preserve its ability to decrease BACE1 expression, without attaining complete BACE1 ablation.…”

Section: Discussionmentioning

confidence: 99%

Novel multifunctional iron chelators of the aroyl nicotinoyl hydrazone class that markedly enhance cellular NAD⁺/NADH ratios

Palanimuthu

Braidy

et al. 2020

British J Pharmacology

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Background and Purpose: Alzheimer's disease (AD) is a multifactorial condition leading to cognitive decline and represents a major global health challenge in ageing populations. The lack of effective AD therapeutics led us to develop multifunctional nicotinoyl hydrazones to target several pathological characteristics of AD.Experimental Approach: We synthesised 20 novel multifunctional agents based on the nicotinoyl hydrazone scaffold, which acts as a metal chelator and a lipophilic delivery vehicle, donating a NAD + precursor to cells, to target metal dyshomeostasis, oxidative stress, β-amyloid (Aβ) aggregation, and a decrease in the NAD + /NADH ratio.Key Results: The most promising compound, 6-methoxysalicylaldehyde nicotinoyl hydrazone (SNH6), demonstrated low cytotoxicity, potent iron (Fe)-chelation efficacy, significant inhibition of copper-mediated Aβ aggregation, oxidative stress alleviation, effective donation of NAD + to NAD-dependent metabolic processes (PARP and sirtuin activity) and enhanced cellular NAD + /NADH ratios, as well as significantly increased median Caenorhabditis elegans lifespan (to 1.46-fold of the control); partly decreased BACE1 expression, resulting in significantly lower soluble amyloid precursor protein-β (sAPPβ) and Aβ 1-40 levels; and favourable blood-brain barrierpermeation properties. Structure-activity relationships demonstrated that the ability of these nicotinoyl hydrazones to increase NAD + was dependent on the electronwithdrawing or electron-donating substituents on the aldehyde-or ketone-derived moiety. Aldehyde-derived hydrazones containing the ONO donor set and electrondonating groups were required for NAD + donation and low cytotoxicity. Conclusions and Implications:The nicotinoyl hydrazones, particularly SNH6, have the potential to act as multifunctional therapeutic agents and delivery vehicles for NAD + precursors for AD treatment.Abbreviations: 59 Fe2-Tf, iron-59 labelled diferric transferrin; 8-OH-QNH, 8-hydroxy-2-quinolinecarboxaldehyde nicotinoyl hydrazone; Aβ, β-amyloid; AcNH1, 4 0 -fluoro-2 0 -hydroxyacetophenone nicotinoyl hydrazone; AcNH2, 5 0 -bromo-2 0 -hydroxyacetophenone nicotinoyl hydrazone; AD, Alzheimer's disease; APP, amyloid precursor protein; BBB, blood-brain barrier; DTPA, diethylenetriaminepentaacetic acid; InNH1, 7-hydroxy-1-indanone nicotinoyl hydrazone; InNH2, 7-hydroxy-6-methyl-1-indanone nicotinoyl hydrazone; InNH3, 4-bromo-7-hydroxy-1-indanone nicotinoyl hydrazone; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NNH, 2-hydroxy-1-naphthaldehyde nicotinoyl hydrazone; PAMPA-BBB, parallel artificial membrane permeability assay of the blood-brain barrier; PCNH, 2-pyridinecarboxaldehyde nicotinoyl hydrazone; PNH, pyridoxal nicotinoyl hydrazone; PrNH1, 5 0 -bromo-2 0

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Lack of β-amyloid cleaving enzyme-1 (BACE1) impairs long-term synaptic plasticity but enhances granule cell excitability and oscillatory activity in the dentate gyrus in vivo

Cited by 10 publications

References 84 publications

Hebbian and Homeostatic Synaptic Plasticity—Do Alterations of One Reflect Enhancement of the Other?

Hebbian and Homeostatic Synaptic Plasticity—Do Alterations of One Reflect Enhancement of the Other?

Amyloid, APP, and Electrical Activity of the Brain

Novel multifunctional iron chelators of the aroyl nicotinoyl hydrazone class that markedly enhance cellular NAD⁺/NADH ratios

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Lack of β-amyloid cleaving enzyme-1 (BACE1) impairs long-term synaptic plasticity but enhances granule cell excitability and oscillatory activity in the dentate gyrus in vivo

Cited by 10 publications

References 84 publications

Hebbian and Homeostatic Synaptic Plasticity—Do Alterations of One Reflect Enhancement of the Other?

Hebbian and Homeostatic Synaptic Plasticity—Do Alterations of One Reflect Enhancement of the Other?

Amyloid, APP, and Electrical Activity of the Brain

Novel multifunctional iron chelators of the aroyl nicotinoyl hydrazone class that markedly enhance cellular NAD+/NADH ratios

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Product

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Novel multifunctional iron chelators of the aroyl nicotinoyl hydrazone class that markedly enhance cellular NAD⁺/NADH ratios