Critical Effects on Akt Signaling in Adult Zebrafish Brain Following Alterations in Light Exposure.

Evidence from human and animal studies indicate that disrupted light cycles leads to alterations of the sleep state, poor cognition, and the risk of developing neuroinflammatory and generalized health disorders. Zebrafish exhibit a diurnal circadian rhythm and are an increasingly popular model in studies of neurophysiology and neuropathophysiology. Here, we investigate the effect of alterations in light cycle on the adult zebrafish brain: we measured the effect of altered, unpredictable light exposure in adult zebrafish telencephalon, homologous to mammalian hippocampus, and the optic tectum, a significant visual processing center with extensive telencephalon connections. The expression of heat shock protein-70 (HSP70), an important cell stress mediator, was significantly decreased in optic tectum of adult zebrafish brain following four days of altered light exposure. Further, pSer473-Akt (protein kinase B) was significantly reduced in telencephalon following light cycle alteration, and pSer9-GSK3ß (glycogen synthase kinase-3ß) was significantly reduced in both the telencephalon and optic tectum of light-altered fish. Animals exposed to five minutes of environmental enrichment showed significant increase in pSer473Akt, which was significantly attenuated by four days of altered light exposure. These data show for the first time that unpredictable light exposure alters HSP70 expression and dysregulates Akt-GSK3ß signaling in the adult zebrafish brain.

Cholinergic Stimulation of the Adult Zebrafish Brain Induces Phosphorylation of Glycogen Synthase Kinase-3 ß and Extracellular Signal-Regulated Kinase in the Telencephalon.

The sequencing of the zebrafish genome, the emergence of powerful gene-editing tools, and the development of in vivo imaging techniques have propelled the economical zebrafish into prominence as a biomedical research model. Neurodegenerative disorders with a cholinergic component, such as Alzheimer's and Parkinson's diseases, are currently modeled using zebrafish. Still, the utility of zebrafish as a research model will not be fully realized until their neurophysiological properties are thoroughly characterized. In mammals, the coupling of cholinergic receptors to the phosphorylation of glycogen synthase kinase-3 ß (GSK3ß) and extracellular signal-regulated kinase 1/2 (ERK1/2) is of critical importance to cognitive processes and imparts protection against neuropathogenic events. Similarly, it is known that cholinergic receptors are required for learning and memory in zebrafish and that in vivo activation of cholinergic receptors induces transient changes in evoked synaptic transmission in the telencephalon. However, the intracellular events mediating cholinergic processes in zebrafish have yet to be elucidated. In the current study, an ex vivo drug treatment assay was used to demonstrate that carbachol (CCh)-mediated cholinergic stimulation of the intact adult zebrafish brain induces phosphorylation of GSK3ß and ERK1/2 in the zebrafish telencephalon. These findings suggest GSK3ß and ERK1/2 may underly cognitive processes in zebrafish.

Overexpression of human apolipoprotein A-I preserves cognitive function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse model of Alzheimer disease.

To date there is no effective therapy for Alzheimer disease (AD). High levels of circulating high density lipoprotein (HDL) and its main protein, apolipoprotein A-I (apoA-I), reduce the risk of cardiovascular disease. Clinical studies show that plasma HDL cholesterol and apoA-I levels are low in patients with AD. To investigate if increasing plasma apoA-I/HDL levels ameliorates AD-like memory deficits and amyloid-ß (Aß) deposition, we generated a line of triple transgenic (Tg) mice overexpressing mutant forms of amyloid-ß precursor protein (APP) and presenilin 1 (PS1) as well as human apoA-I (AI). Here we show that APP/PS1/AI triple Tg mice have a 2-fold increase of plasma HDL cholesterol levels. When tested in the Morris water maze for spatial orientation abilities, whereas APP/PS1 mice develop age-related learning and memory deficits, APP/PS1/AI mice continue to perform normally during aging. Interestingly, no significant differences were found in the total level and deposition of Aß in the brains of APP/PS1 and APP/PS1/AI mice, but cerebral amyloid angiopathy was reduced in APP/PS1/AI mice. Also, consistent with the anti-inflammatory properties of apoA-I/HDL, glial activation was reduced in the brain of APP/PS1/AI mice. In addition, Aß-induced production of proinflammatory chemokines/cytokines was decreased in mouse organotypic hippocampal slice cultures expressing human apoA-I. Therefore, we conclude that overexpression of human apoA-I in the circulation prevents learning and memory deficits in APP/PS1 mice, partly by attenuating neuroinflammation and cerebral amyloid angiopathy. These findings suggest that elevating plasma apoA-I/HDL levels may be an effective approach to preserve cognitive function in patients with AD.