Overexpression of Hsp27 ameliorates symptoms of Alzheimer's disease in APP/PS1 mice.

Hsp27 belongs to the small heat shock protein family, which are ATP-independent chaperones. The most important function of Hsp27 is based on its ability to bind non-native proteins and inhibit the aggregation of incorrectly folded proteins maintaining them in a refolding-competent state. Additionally, it has anti-apoptotic and antioxidant activities. To study the effect of Hsp27 on memory and synaptic functions, amyloid-ß (Aß) accumulation, and neurodegeneration, we generated transgenic mice overexpressing human Hsp27 protein and crossed with APPswe/PS1dE9 mouse strain, a mouse model of Alzheimer's disease (AD). Using different behavioral tests, we found that spatial learning was impaired in AD model mice and was rescued by Hsp27 overexpression. Electrophysiological recordings have revealed that excitability of neurons was significantly increased, and long-term potentiation (LTP) was impaired in AD model mice, whereas they were normalized in Hsp27 overexpressing AD model mice. Using anti-amyloid antibody, we counted significantly less amyloid plaques in the brain of APPswe/PS1dE9/Hsp27 animals compared to AD model mice. These results suggest that overexpression of Hsp27 protein might ameliorate certain symptoms of AD.

Interplay between glycogen synthase kinase-3ß and tau in the cerebellum of Hsp27 transgenic mouse.

The association between heat shock protein 27 (Hsp27) and hyperphosphorylated tau has gained attention for more than a decade, but it has never been explored in vivo. In the present study, we found that tau phosphorylated at S396/404 (PHF-1) and S262 sites was significantly increased in the cerebellum of Hsp27 transgenic mice, which was concomitant with increased glycogen synthase kinase-3ß (GSK3ß) phosphorylated at Y216 and decreased GSK3ß phosphorylated at S9. Neither 70-kDa ribosomal protein S6 kinase (p70S6K; total p70S6K, p70S6K at T389, and p70S6K at T421/S424) nor protein phosphatase PP2A (total PP2A, PP2A at Y307, methylated or demethylated PP2A) was changed. This suggests that the increased tau phosphorylation at S396/404 and S262 sites may be induced by Hsp27 through enhancement of GSK3ß activity in the mouse cerebellum.

Neuroprotective effect of small heat shock protein, Hsp27, after acute and chronic alcohol administration.

Alcohol induces degeneration of neurons and inhibits neurogenesis in the brain. Small heat shock proteins are able to protect neurons in cerebral ischemia and oxidative stress. In this study, we investigated the neuroprotective effect of small heat shock protein, Hsp27, after acute and chronic ethanol administrations using transgenic mice overexpressing the human Hsp27 protein. Transgenic mice and wild-type littermates were injected with 2 g/kg ethanol intraperitoneally, and then motor coordination and muscle strength were analyzed using different behavioral tests, such as footprint analysis, balance beam, and inverted screen tests. Ethanol-injected transgenic mice showed similar footprints to control saline-injected mice, did not fall of the beam, and were able to climb to the top of the inverted screen, while wild-type mice showed ataxia and incoordination after ethanol injection. The effect of Hsp27 on chronic ethanol consumption was also investigated. Drinking water of mice was replaced by a 20% ethanol solution for 5 weeks, and then brain sections were stained with Fluoro Jade C staining. We found significantly lesser amount of degenerating neurons in the brain of ethanol-drinking transgenic mice compared to wild-type mice. We conclude that Hsp27 can protect neurons against the acute and chronic toxic effects of ethanol.