New discoveries are one step closer with a new application using okadaic acid in Alzheimer’s research. Alzheimer’s disease is difficult to model in non-human animals. Recently, a collaboration between Indian and American researchers proposed a treatment combination that could produce rats with more biomarkers of Alzheimer’s disease than previous models.
Hypoxia increases the amount of misfolded amyloid beta aggregates in the brain, a well-known biomarker of Alzheimer’s disease. However, hypoxia does not cause tau tangles, which is another biomarker of Alzheimer’s disease. Okadaic acid is a toxin that is known for causing diarrhetic shellfish poisoning. It selectively inhibits phosphatases, so it is often used as a research chemical to study phosphorylation. As it turns out, in the brain it hyperphosphorylates tau, which causes it to tangle.
A combination of hypoxia and okadaic acid treatment therefore should produce rats with more biomarkers of Alzheimer’s disease than either treatment alone.
This collaborative research team microinjected okadaic acid into live rat brains, then placed the rats in a hypoxic chamber with 10% oxygen (atmosphere contains about 21%) for three days. The treated rats fared worse at an electrical shock avoidance test and a water maze memory test.
The team then sacrificed the rats and analyzed their brain biochemistry. As predicted, hypoxia increased the amount of amyloid beta aggregates in the rat brains, and okadaic acid increased the number of hyperphosphorylated tau tangles. Rats that received the combination treatment also had decreased acetylcholine esterase activity and increased oxidative damage, which are also biochemical hallmarks of Alzheimer’s disease.
This combination treatment of hypoxia plus okadaic acid in rats should be useful for further advancing the research into Alzheimer’s disease.
Kaushal A, Wani WY, Bal A, Gill KD, Kaur J. Okadaic acid and hypoxia induced dementia model of Alzheimer’s type in rats. 2019. Neurotoxicity Research. PMID: 30729451