Amyloid-β precursor protein mutant zebrafish exhibit seizure susceptibility that depends on prion protein

Kanyo, Richard; Leighton, Patricia L.A.; Neil, Gavin J.; Locskai, Laszlo F.; Allison, W. Ted

doi:10.1016/j.expneurol.2020.113283

Cited by 13 publications

(10 citation statements)

References 65 publications

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“…For example, morpholino knockdown of zebrafish Appb has variously been reported to affect convergent-extension during gastrulation (Joshi et al, 2009), axon outgrowth of spinal motor neurons (Abramsson et al, 2013; Song and Pimplikar, 2012), hindbrain neurogenesis (Banote et al, 2016), or cerebrovascular development (Luna et al, 2013). Given that our observations are in line with other recent studies that do not find large developmental phenotypes for zebrafish app mutants (Banote et al, 2020; Chebli et al, 2021; Kanyo et al, 2020), together with the wildly divergent abnormalities described for morpholino knockdown of the same appb gene, we suggest these morpholino based observations are experimental artefacts.…”

Section: Discussionsupporting

confidence: 91%

“Genetic and chemical disruption of Amyloid Precursor Protein processing impairs zebrafish sleep maintenance”

Özcan

Lim

Rihel

2022

Preprint

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Sleep-wake disturbances are among the earliest symptoms of Alzheimer's disease (AD) and contribute to disease severity. Since a major driver of AD— the accumulation of amyloid-beta (Aβ) in the brain— is modulated by sleep, a "vicious" feedforward cycle has been proposed in which Aβ buildup disrupts sleep, leading to more Aβ secretion and further worsening of sleep and AD. Consistent with this idea, mouse models of AD develop early sleep phenotypes, and sleep is acutely modulated by exogenous Aβ. However, these overexpression paradigms leave unclear whether endogenous Aβ signaling contributes to sleep regulation. To tackle this question, we generated loss of function mutations in the zebrafish orthologs of Amyloid Precursor Protein (APP) and monitored larval sleep behavior. Larvae with mutations in appa had reduced waking activity levels but normal sleep patterns, while larvae that lacked appb had reduced sleep due to an inability to maintain sleep bout durations. In addition, larvae exposed to the γ-secretase inhibitor DAPT, which inhibits Aβ production from APP, also have shorter sleep bouts at night. Although γ-secretase inhibition impacts the proteolytic cleavage of many proteins, appb mutants were insensitive to the sleep bout shortening effects of DAPT, suggesting that loss of γ-secretase dependent proteolytic cleavage products of Appb are responsible for the reduced sleep maintenance phenotypes. These results are consistent with a model in which endogenous Aβ directly modulates sleep in zebrafish and supports the idea that sleep disturbances may be a useful early-onset biomarker for AD.

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Section: Discussionsupporting

confidence: 91%

“Genetic and chemical disruption of Amyloid Precursor Protein processing impairs zebrafish sleep maintenance”

Özcan

Lim

Rihel

2022

Preprint

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“…Further, of particular interest is the decreased relative transcript abundance of pcdh19 , a non-clustered protocadherin which has been shown to be one of the highest genetic risk factors relating to epilepsy [ 51 ]. Mice lacking PrP C have been shown to be at an increased risk of seizures [ 52 ] and we have also shown this in our prp1 −/- and prp2 −/- knockout zebrafish [ 17 , 53 ]. This adds to the increasing amount of data showing PrP C plays a neuroprotective role in vertebrates; this may explain why many phenotypes now becoming apparent occur only after stress is put on the animal.…”

Section: Discussionsupporting

confidence: 66%

Transcriptomic analysis of zebrafish prion protein mutants supports conserved cross-species function of the cellular prion protein

Pollock

Leighton

Neil

et al. 2021

Prion

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“…The same zebrafish larvae being placed in the 96-well plate the day prior for CaMPARI analysis were objectively quantified for locomotion using Basler GenICaM (Basler acA 1300-60) scanning camera (75-mm f2.8 C-mount lens) and EthoVision XT-11.5 software by Noldus (Wageningen, Netherlands) as described previously 74 . Briefly, larvae were acclimatized for 3 h and one hour of movement was recorded from each individual larvae in each well.…”

Section: Methodsmentioning

confidence: 99%

Medium-throughput zebrafish optogenetic platform identifies deficits in subsequent neural activity following brief early exposure to cannabidiol and Δ9-tetrahydrocannabinol

Kanyo

Amin

Locskai

et al. 2021

Sci Rep

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In light of legislative changes and the widespread use of cannabis as a recreational and medicinal drug, delayed effects of cannabis upon brief exposure during embryonic development are of high interest as early pregnancies often go undetected. Here, zebrafish embryos were exposed to cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) until the end of gastrulation (1–10 h post-fertilization) and analyzed later in development (4–5 days post-fertilization). In order to measure neural activity, we implemented Calcium-Modulated Photoactivatable Ratiometric Integrator (CaMPARI) and optimized the protocol for a 96-well format complemented by locomotor analysis. Our results revealed that neural activity was decreased by CBD more than THC. At higher doses, both cannabinoids could dramatically reduce neural activity and locomotor activity. Interestingly, the decrease was more pronounced when CBD and THC were combined. At the receptor level, CBD-mediated reduction of locomotor activity was partially prevented using cannabinoid type 1 and 2 receptor inhibitors. Overall, we report that CBD toxicity occurs via two cannabinoid receptors and is synergistically enhanced by THC exposure to negatively impact neural activity late in larval development. Future studies are warranted to reveal other cannabinoids and their receptors to understand the implications of cannabis consumption on fetal development.

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Amyloid-β precursor protein mutant zebrafish exhibit seizure susceptibility that depends on prion protein

Cited by 13 publications

References 65 publications

“Genetic and chemical disruption of Amyloid Precursor Protein processing impairs zebrafish sleep maintenance”

“Genetic and chemical disruption of Amyloid Precursor Protein processing impairs zebrafish sleep maintenance”

Transcriptomic analysis of zebrafish prion protein mutants supports conserved cross-species function of the cellular prion protein

Medium-throughput zebrafish optogenetic platform identifies deficits in subsequent neural activity following brief early exposure to cannabidiol and Δ9-tetrahydrocannabinol

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