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Sep 6, 2012

Alzheimer’s Disease Mice Retain Their Cognitive Function

  • Deleting a single enzyme from the brains of a mouse model of aggressive Alzheimer’s disease has led to the most significant reduction in amyloid β (Aβ peptide) achieved to date, and may represent a valuable new therapeutic approach to treating the disease, scientists claim. The Ohio State University-led team found that genetically deleting JNK3 in FAD mice led to dramatic improvements that allowed the animals to retain 80% normal cognitive function by the time they were a year old, and retain 86% the numbers of neurons found in wild-type mice. These benefits were associated with a 90% lower level of Aβ (Aβ42) deposits accumulating in the brains of the JNK3-deficient mice than in the animals that still expressed JNK3.

    Sung Ok Yoon, M.D., and colleagues, found that JNK3 activity is increased both in human AD patients and in FAD mice. These animals express mutant human amyloid precursor protein (APP) and PS1 genes, and produce increased levels of Aβ42 and Aβ40. Having demonstrated that deleting JNK3 in the mouse brain significantly holds back the development of Alzheimer’s disease, the researchers analyzed what effects JNK3 may have at the molecular level. They found, surprisingly, that while neuronal expression of genes necessary for new protein production was significantly lower in the Alzheimer’s disease mouse brains than normal mouse brains, shutting down JNK3 allowed the neurons to ramp up their protein production back to near normal levels. Importantly, JNK3 was found to result in phosphorylation of APP in neurons, causing it to be internalized into endosomal compartments and processed into Aβ.

    The researchers then looked more closely at the effects of Aβ production in the brain and found that the peptides activate AMP kinase (AMPK), which in turn leads to mTOR pathway blockade. This triggers endoplasmic reticulum (ER) stress, shutting down protein production by neurons, which leads to neuronal cell death. Interestingly, Yoon points out, prior work had already indicated that ER stress itself can cause JNK3 activation. And, in fact, the Ohio team’s further studies using mouse brain tissue confirmed that treatment with either an mTOR inhibitor or a drug that induces ER stress was capable of dramatically increasing Aβ production, as long as JNK3 was present.

    The combined results from their studies enabled the investigators to come up with a model of Alzheimer’s disease based on the premise that JNK3 activation maintains a positive feedback loop culminating in continued production of Aβ42. In essence, an as yet unknown physiological trigger increases JNK3 activity, which leads to initial production of Aβ peptides from APP. The Aβ peptides stimulate AMPK, which dampens mTOR signalling and protein production by neurons, leading to ER stress, which increases JNK3 activity yet further, and results in production of yet more Aβ, which further propagates the cycle.

    “Our findings suggest that JNK3 activation is central to the development of AD pathology by exacerbating metabolic stress that is induced by Aβ42 accumulation,” the authors write in their published paper in Neuron“This study thus identifies JNK3 as a promising new target of therapeutic intervention for Alzheimer’s disease.”

    The authors admit that the initial trigger for generating ER stress remains elusive. However, professor Yoon says, “The fact that we found that protein synthesis is hugely affected by Alzheimer’s disease opens up a door to let us try a variety of drugs that are already developed for other chronic progressive diseases that share this commonality of affected protein production.”

    Professor Yoon et al., report their findings in a paper titled “JNK3 Perpetuates Metabolic Stress Induced by Aβ Peptides.”


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