Human brain-derived Aβ oligomers bind to synapses and disrupt synaptic activity in a manner that requires APP

Walsh, Dominic M.; Wang, Zemin; Jackson, Rosemary J.; Walter, Taylor M.; Moreno, Arturo J.; Li, Wen; Li, Shaomin; Frosch, Matthew P.; Slutsky, Inna; Young‐Pearse, Tracy L.; Spires‐Jones, Tara L.

doi:10.1101/135673

Cited by 32 publications

(45 citation statements)

References 106 publications

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“…On the other hand, our results show that LTP is reduced in brain slices from APP-/-mice. This is in agreement with previous studies showing that the LTP induced by one TBS is reduced in APP-/-at the SC-CA1 synapses (Dawson et al, 1999;Seabrook et al, 1999;Ring et al, 2007) but not at the perforant path-granule cell (DG) synapse that we did not study here (Jedlicka et al, 2012), Such inhibition was however not observed by other investigators (Wang et al, 2017),…”

Section: Alteration Of Gaba Release and Gaba Markers In App Deficientsupporting

confidence: 94%

Amyloid Precursor Protein (APP) Controls the Expression of the Transcriptional Activator Neuronal PAS Domain Protein 4 (NPAS4) and Synaptic GABA Release

Opsomer¹,

Contino²,

Perrin

et al. 2020

eNeuro

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The Amyloid Precursor Protein (APP) has been extensively studied as the precursor of the βamyloid peptide (Aβ) peptide, the major component of the senile plaques found in the brain of Alzheimer's disease (AD) patients. However, the function of APP per se in neuronal physiology remains to be fully elucidated. APP is expressed at high levels in the brain. It resembles a cell adhesion molecule or a membrane receptor, suggesting that its function relies on cell-cell interaction and/or activation of intracellular signaling pathways. In this respect, the APP intracellular domain (AICD) was reported to act as a transcriptional regulator. Here, we used a transcriptome-based approach to identify the genes transcriptionally regulated by APP in the rodent embryonic cortex and upon maturation of primary cortical neurons. Surprisingly, the overall transcriptional changes were subtle, but a more detailed analysis pointed to genes clustered in neuronal-activity dependent pathways. In particular, we observed a decreased transcription of Neuronal PAS domain protein 4 (NPAS4) in APP-/-neurons. NPAS4 is an inducible transcription factor (ITF) regulated by neuronal depolarization. The down-regulation of NPAS4 co-occurs with an increased production of the inhibitory neurotransmitter GABA and a reduced expression of the GABA A receptors alpha1. CRISPR-Cas-mediated silencing of NPAS4 in neurons led to similar observations. Patch-clamp investigation did not reveal any functional decrease of GABA A receptors activity, but LTP measurement supported an increased GABA component in synaptic transmission of APP-/-mice. Together, NPAS4 appears to be a downstream target involved in APP-dependent regulation of inhibitory synaptic transmission.

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Section: Alteration Of Gaba Release and Gaba Markers In App Deficientsupporting

confidence: 94%

Amyloid Precursor Protein (APP) Controls the Expression of the Transcriptional Activator Neuronal PAS Domain Protein 4 (NPAS4) and Synaptic GABA Release

Opsomer¹,

Contino²,

Perrin

et al. 2020

eNeuro

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show abstract

“…Because recent studies indicated that high nanomolar concentrations of extracellular oA␤ 42 require APP to impair LTP and memory (Puzzo et al, 2017;Wang et al, 2017), we tested whether the plasticity-enhancing effect of extracellular picomolar concentrations of oA␤ 42 was APP dependent. We used APP-KO mice to determine whether the absence of endogenous APP prevented 200 pM oA␤ 42 to exert its effects on PPF and LTP.…”

Section: Effect Of Picomolar Concentrations Of Oa␤ 42 On Short-term Amentioning

confidence: 99%

Neuromodulatory Action of Picomolar Extracellular Aβ42 Oligomers on Presynaptic and Postsynaptic Mechanisms Underlying Synaptic Function and Memory

et al. 2019

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Failure of anti-amyloid-␤ peptide (A␤) therapies against Alzheimer's disease (AD), a neurodegenerative disorder characterized by high amounts of the peptide in the brain, raised the question of the physiological role of A␤ released at low concentrations in the healthy brain. To address this question, we studied the presynaptic and postsynaptic mechanisms underlying the neuromodulatory action of picomolar amounts of oligomeric A␤ 42 (oA␤ 42) on synaptic glutamatergic function in male and female mice. We found that 200 pM oA␤ 42 induces an increase of frequency of miniature EPSCs and a decrease of paired pulse facilitation, associated with an increase in docked vesicle number, indicating that it augments neurotransmitter release at presynaptic level. oA␤ 42 also produced postsynaptic changes as shown by an increased length of postsynaptic density, accompanied by an increased expression of plasticity-related proteins such as cAMPresponsive element binding protein phosphorylated at Ser133, calcium-calmodulin-dependent kinase II phosphorylated at Thr286, and brain-derived neurotrophic factor, suggesting a role for A␤ in synaptic tagging. These changes resulted in the conversion of early into late long-term potentiation through the nitric oxide/cGMP/protein kinase G intracellular cascade consistent with a cGMP-dependent switch from short-to long-term memory observed in vivo after intrahippocampal administration of picomolar amounts of oA␤ 42. These effects were present upon extracellular but not intracellular application of the peptide and involved ␣7 nicotinic acetylcholine receptors. These observations clarified the physiological role of oA␤ 42 in synaptic function and memory formation providing solid fundamentals for investigating the pathological effects of high A␤ levels in the AD brains.

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“…In addition, we report beneficial activity of NGP 555 directed at synaptic function. Mechanistically, these data can be explained by the direct decrease in the production Ab 42 as previously described [45,46]. Alternately, reports showing beneficial changes on synapse function by disrupting g-secretase activity may occur via processing of other substrates involved in synaptic function [47][48][49][50].…”

Section: Discussionmentioning

confidence: 69%

NGP 555, a γ‐secretase modulator, shows a beneficial shift in the ratio of amyloid biomarkers in human cerebrospinal fluid at safe doses

Kounnas

Durakoglugil

Herz

et al. 2019

A&D Transl Res & Clin Interv

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Introduction Currently, there is no cure for Alzheimer's disease (AD), and it is widely accepted that AD is a complex disease with multiple approaches necessary to prevent and treat the disease. Methods Using amyloid biomarkers in human cerebrospinal fluid, pharmacokinetic, safety, and metabolism studies, we investigate the properties of NGP 555, γ‐secretase modulator, for the first time in human clinical trials. Results Our preclinical and clinical studies combined show beneficial effects with NGP 555 on synaptic response and amyloid cerebrospinal fluid biomarkers while avoiding negative side effects. Importantly, pharmacokinetic and pharmacodynamic parameters combined with safety outcomes indicate that NGP 555 penetrates the blood‐brain barrier and increases the ratio of amyloid‐β peptide Aβ37 and Aβ38 compared with that of Aβ42, establishing a proof of target engagement in humans in a 14 day, once‐daily oral dosing trial. Discussion In humans, NGP 555 has demonstrated a beneficial shift in the production of Aβ37 and Aβ38 versus Aβ42 biomarker levels in the cerebrospinal fluid while maintaining an adequate safety profile. The overall clinical goal is to achieve an optimal balance of efficacy for altering amyloid‐β peptide (Aβ) biomarkers while maintaining a safe profile so that NGP 555 can be given early in AD to prevent production of Aβ42 and accumulation of amyloid plaques, in an effort to prevent aggregation of tau and destruction of neurons and synapses resulting in cognitive decline.

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Human brain-derived Aβ oligomers bind to synapses and disrupt synaptic activity in a manner that requires APP

Cited by 32 publications

References 106 publications

Amyloid Precursor Protein (APP) Controls the Expression of the Transcriptional Activator Neuronal PAS Domain Protein 4 (NPAS4) and Synaptic GABA Release

Amyloid Precursor Protein (APP) Controls the Expression of the Transcriptional Activator Neuronal PAS Domain Protein 4 (NPAS4) and Synaptic GABA Release

Neuromodulatory Action of Picomolar Extracellular Aβ42 Oligomers on Presynaptic and Postsynaptic Mechanisms Underlying Synaptic Function and Memory

NGP 555, a γ‐secretase modulator, shows a beneficial shift in the ratio of amyloid biomarkers in human cerebrospinal fluid at safe doses

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