Biological Psychiatry reports new research on the therapy with an inhibitor of 12/15-lipoxygenase, an enzyme elevated in patients with Alzheimer’s disease (AD), reverses cognitive decline, and neuropathology in an AD mouse model. The outcome was recognized after the AD-like phenotype was established in the mice, which is promising for its possible therapeutic use.
The research by Domenico Praticὸ, senior author, and colleagues at Temple University, offers potential for new treatment for individuals with AD, who have no sufficient therapy options presently. Focusing on prevention of the disease by reducing the levels of proteins that cause brain plaques and tangles and kill nerve cells has been the attention in the past..
Editor of Biological Psychiatry, John Krystal said, “In this exciting new study, the authors provide support for a new experimental treatment approach that works by helping nerve cells digest toxic proteins that might otherwise cause cell death.”
Antonio Di Meco, first author, and colleagues used a triple transgenic (3xTg) mouse model that displays an AD-like phenotype, including cognitive decline, and Aβ and tau neuropathology characteristic of the disease in humans. The researchers had already shown that early application of the 12/15-lipoxygenase inhibitor PD146176 could prohibit the onset of these features in mice. To achieve a more real-world scenario in this research, they waited until the mice were one year old before administering the drug.
Pratico said, “We show for the first time that selective pharmacologic inhibition of the 12/15-lipoxygenase enzyme rescues the entire AD-like phenotype.” 3xTg mice that were untreated showed defective memory and learning, however 3xTg mice that were administered PD146176 for three months were identical to normal mice in a memory test. In the same mice, the researchers found that PD146176 therapy dramatically reduced the levels of tau proteins and Aβ.
Inhibition of 12/15-lipoxygenase stimulated autophagy, the body’s natural kill system for cells. The activation was correlated with the drop of tau levels. This suggests that the inhibitor works by re-activating the neuronal autophagy machinery to clear cellular buildup of tau proteins.
The conclusion indicates that pharmacological inhibition of 12/15-lipoxygenase reverses memory and learning impairments and reduces Aβ and tau neuropathology. Pratico said, “Our findings have important translational value since they establish this protein enzyme as a novel and viable therapeutic target with real disease-modifying potential for AD.”