Brain Intraventricular Injection of Amyloid-β in Zebrafish Embryo Impairs Cognition and Increases Tau Phosphorylation, Effects Reversed by Lithium

Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder with no effective treatment and commonly diagnosed only on late stages. Amyloid-β (Aβ) accumulation and exacerbated tau phosphorylation are molecular hallmarks of AD implicated in cognitive deficits and synaptic and neuronal loss. The Aβ and tau connection is beginning to be elucidated and attributed to interaction with different components of common signaling pathways. Recent evidences suggest that non-fibrillary Aβ forms bind to membrane receptors and modulate GSK-3β activity, which in turn phosphorylates the microtubule-associated tau protein leading to axonal disruption and toxic accumulation. Available AD animal models, ranging from rodent to invertebrates, significantly contributed to our current knowledge, but complementary platforms for mechanistic and candidate drug screenings remain critical for the identification of early stage biomarkers and potential disease-modifying therapies. Here we show that Aβ1–42 injection in the hindbrain ventricle of 24 hpf zebrafish embryos results in specific cognitive deficits and increased tau phosphorylation in GSK-3β target residues at 5dpf larvae. These effects are reversed by lithium incubation and not accompanied by apoptotic markers. We believe this may represent a straightforward platform useful to identification of cellular and molecular mechanisms of early stage AD-like symptoms and the effects of neuroactive molecules in pharmacological screenings.

Comparing the effect of the novel ionic cocrystal of lithium salicylate proline (LISPRO) with lithium carbonate and lithium salicylate on memory and behavior in female APPswe/PS1dE9 Alzheimer's mice

“…Our study confirms previous studies showing a beneficial effect of lithium in animal models of AD and AD patients, while also highlighting the potential benefit of LISPRO. Although a few studies reported no effect of lithium chloride on Aβ levels (Caccamo, Oddo, Tran, & LaFerla, ; Feyt et al, ) or even neurodegeneration induced by tau suppression (Lei et al, ), the overriding evidence indicates that lithium treatment effectively reduces extracellular β‐amyloid (Habib et al, ; Trujillo‐Estrada et al, ) and tau hyperphosphorylation in cell culture and animal models of AD (Nery et al, ). Likewise, intracerebroventricular injection of Aβ in zebrafish embryo impairs cognition which was successfully reversed by lithium administration (Nery et al, ).…”

Analysis of 17 neurotransmitters, metabolites and precursors in zebrafish through the life cycle using ultrahigh performance liquid chromatography–tandem mass spectrometry

“…Zebrafish shows genetic and anatomic conservation with both mice and humans and a high degree of genetic homology [2,3]. In addition, the role of different excitatory and inhibitory neurotransmitter systems in the zebrafish has been reviewed by Rico et al [4,5] showing that all human neurotransmitters are preserved in zebrafish with similar biological roles [6][7][8][9][10][11][12][13][14][15].…”

The interactions of p53 with tau and Aß as potential therapeutic targets for Alzheimer’s disease

“…A connection between soluble Aβ and tau protein phosphorylation is well documented in AD pathology. Accumulating evidence indicates that soluble Aβ induces tau phosphorylation (Jin et al, 2011;Bloom, 2014;Stancu et al, 2014;Nery et al, 2014), and GSK-3 is recognized as an important link between Aβ and tau pathologies ( Figure 2; Huang and Jiang, 2009;Jazvinšćak Jembrek et al, 2013). Accumulation of Aβ oligomers inhibits phosphatidylinositol-3-kinase (PI-3K) and…”

“…Injection of Aβ42 in the hindbrain ventricle of zebrafish embryos reduced cognitive abilities and promoted tau phosphorylation at GSK-3β specific sites at larval stage. These specific behavioural and molecular effects were reversed by lithium chloride, a GSK-3β inhibitor (Nery et al, 2014). In a double-transgenic mouse model expressing low levels of Arctic mutant Aβ that mimics the near physiological levels of soluble Aβ found early in AD, soluble Aβ forms facilitate cognitive impairment and profoundly influence the progression of tau pathology (Chabrier et al, 2012).…”