Neuroprotective Effects of Sphingosine Kinase 2 in Mouse Models of Alzheimer’s Disease

Post by Shireen Parimoo

What's the science?

Alzheimer’s disease (AD) is a neurodegenerative disease most commonly characterized by memory deficits and the accumulation of amyloid-beta (Aβ) plaques in the brain. The hippocampus, which is important for memory and spatial navigation, is one of the brain regions that is severely affected by Aβ pathology in AD. Studies have linked AD to lower concentrations of hippocampal sphingosine-1-phosphate (S1P), a signaling lipid that is important for glial cell survival, and sphingosine kinase 2 (SK2), an enzyme responsible for producing S1P. Although this suggests that SK2 and S1P may be important for normal brain functioning, SK2 has also been shown to facilitate the formation of Aβ plaques. This week in The Journal of Neuroscience, Lei and colleagues investigated the effects of SK2 deletion on the structural and functional characteristics of hippocampal neurons in mouse models of AD.

How did they do it?

Transgenic mice with SK2 deletion (SK2D) or without SK2 deletion (SK2+/+) were cross-bred with AD mice (J20) to produce four different lines of transgenic mice: (i) SK2+/+ mice, (ii) SK2D mice, (iii) J20-SK2+/+ or J20 mice, and (iv) J20-SK2D mice. The J20 mice over-express the human amyloid precursor protein transgene, resulting in high concentrations of Aβ proteins and memory deficits, like in AD. The authors used immunohistochemistry and enzyme-linked immunoassays to examine Aβ pathology, including plaque number, burden, and Ab concentration in the hippocampal tissue of 8- and 13-month-old mice. To determine the effects of Aβ pathology and SK2 loss on behavior, 7- and 12-month-old mice completed several cognitive tests, including the Y-maze (spatial memory), the social preference test (social exploration), the social novelty test (social recognition memory for novel vs familiar mice), and the novel object recognition test (object recognition memory for novel vs familiar objects).

The authors then examined the hippocampal volume and neuronal density in 7- and 12-month-old mice. They further identified potential causes of volume and density changes using immunofluorescence microscopy and Western blotting to characterize de-myelination, axonal degeneration, and oligodendrocyte (glial cells produce myelin) density in the hippocampus. Finally, electroencephalography was used to determine the effect of SK2 deletion on functional hippocampal activity in 13-month-old mice. This included measures of epileptiform activity (transient, high-frequency activity), oscillatory power modulation in the theta (4-12 Hz) and gamma (25-100 Hz) frequency bands, and theta-gamma phase-amplitude coupling.

What did they find?

Plaque pathology was not observed in the wild-type (WT) or SK2+/+ mice. However, there was greater plaque pathology in J20 mice at 13 months old than at 8 months old. Moreover, J20 mice had greater plaque pathology and Aβ concentration than J20-SK2D mice. Consistent with this, hippocampal epileptiform activity was higher in the J20 mice compared to the J20-SK2D mice, but absent in the WT and SK2D mice. Oscillatory power was also lower in J20-SK2D mice compared to the other mouse lines. Thus, the absence of SK2 reduces plaque burden, hippocampal oscillatory power, and epileptiform activity in AD mice. In contrast, hippocampal volume was lower in the J20-SK2D mice compared to the WT mice at 13 months old. Furthermore, hippocampal neurons in the 13-month-old J20-SK2D mice were less myelinated and had fewer oligodendrocytes compared to the WT mice. This means that the accumulation of Aβ plaques in the absence of SK2 likely resulted in fewer oligodendrocytes, leading to demyelination and smaller hippocampi in the AD-like mice.

Cognitive performance was also affected by SK2 deletion, as the J20-SK2D mice performed at chance levels on the Y-maze test whereas the WT, SK2D, and J20 mice performed above chance. Similarly, the J20-SK2D mice had lower performance on the social novelty test. However, they did not differ from other mice on the social preference test, suggesting that their deficit is specific to memory rather than social exploration. Thus, spatial memory and social recognition memory are particularly impaired in mice with both Aβ burden and SK2 deletion.

What's the impact?

This study is the first to demonstrate the role of SK2 in Aβ formation in vivo and the resulting abnormal activity in the hippocampus. At the same time, however, the study establishes the adverse effects of SK2 deficiency on hippocampal structure, myelination, and cognitive performance. These findings also provide further insight into the importance of oligodendrocytes in maintaining normal hippocampal function and pave the way for future research to investigate how the loss of glial cell function contributes to pathology in neurodegenerative diseases.

Lei et al. Sphingosine kinase 2 potentiates amyloid deposition but protects against hippocampal volume loss and demyelination in a mouse model of Alzheimer’s disease. The Journal of Neuroscience (2019). Access the original scientific publication here.