AsianScientist (Aug. 23, 2012) – Although the complete mechanism still eludes researchers, studies have shown that the accumulation of β-amyloid – a protein that is toxic to nerve cells – may be one of the underlying causes of Alzheimer’s disease.
β-amyloid is formed by the activity of several enzymes, including one called BACE1. Most Alzheimer’s disease patients have elevated levels of BACE1, which in turn leads to more brain damaging β-amyloid protein.
In a paper published recently in The Journal of Neuroscience, researchers at Sanford-Burnham Medical Research Institute in the United States found that BACE1 does more than just help cells produce β-amyloid – it also regulates another cellular process that contributes to memory loss.
This means is that inhibiting the enzymatic function of BACE1 to prevent or treat Alzheimer’s disease would not be enough to limit BACE1, as researchers will have to prevent cells from producing it at all.
“Memory loss is a big problem; not just in Alzheimer’s disease, but also in the normal aging population,” said senior author Prof. Huaxi Xu. “In this study, we wanted to better understand how BACE1 plays a role in memory loss, apart from β-amyloid production.”
To understand the role of BACE1 in memory loss, Xu and his team used a mouse model that was engineered to produce human BACE1.
Mice produce a different type of β-amyloid, one that is far less toxic than the human version. Therefore, in this system, the researchers could look solely at how BACE1 functions, independent from β-amyloid formation.
If BACE1 only acted to produce β-amyloid, the researchers would expect to see no effect when mice produce human BACE1 since mouse β-amyloid is not very toxic. Instead, they saw that the enzyme still impaired learning and memory, indicating a secondary function at work.
Many years ago, scientists found that protein kinase A (PKA), a protein in the brain better known for directing cellular metabolism, also plays an important role in memory formation.
In this study, Xu and colleagues found that BACE1 disrupts the cell’s production of other molecules required for PKA function. Through this mechanism, BACE1 inactivates PKA and inhibits memory formation in mice, even in the absence of neurotoxic β-amyloid.
“So BACE1 is a double whammy when it comes to memory,” Xu said. “But that also means that a therapy that targets BACE1 could be a double punch against Alzheimer’s disease, and even just normal aging-related memory loss. That’s why we’re now looking for ways to block BACE1 expression in the brain.”
The article can be found at: Chen Y et al. (2012) Alzheimer’s β-Secretase (BACE1) Regulates the cAMP/PKA/CREB Pathway Independently of β-Amyloid.
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Source: Sanford-Burnham Medical Research Institute.
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