Enzyme Known For Generating Toxic Brain Plaques In Alzheimer's Disease Likewise Makes Additional Memory And Cognitive Shortfalls

The underlying causes of Alzheimer's disease are not fully understood, but a good deal of evidence points to the accumulation of β-amyloid, a protein that's toxic to nerve cells. 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 in The Journal of Neuroscience, researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) found that BACE1 does more than just help produce β-amyloid - it also regulates another cellular process that contributes to memory loss. This means that just inhibiting BACE1's enzymatic activity as a means to prevent or treat Alzheimer's disease isn't enough - researchers will have to prevent cells from making it at all.

"Memory loss is a big problem - not just in Alzheimer's disease, but also in the normal aging population," said Huaxi Xu, Ph.D., professor in Sanford-Burnham's Del E. Webb Neuroscience, Aging, and Stem Cell Research Center and senior author of the study. "In this study, we wanted to better understand how BACE1 plays a role in memory loss, apart from β-amyloid production."

To do this, Xu and his team used a mouse model that produces human BACE1. Mice produce a different type of β-amyloid, one that's far less toxic than the human version. So, in this system, they 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 isn't very toxic, extra BACE1 would be no big deal. Instead, they saw that the enzyme still impaired learning and memory, indicating a secondary function at work.

If it's not producing β-amyloid, what is BACE1 doing? Many years ago, scientists found that a protein in the brain - protein kinase A (PKA), 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. By that mechanism, BACE1 inactivates PKA and therefore 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."

Neurotransmitter Production looks To Be decelerated By 'Alzheimer Protein'

RUB researchers analyze proteome of cells

How abnormal protein deposits in the brains of Alzheimer's patients disrupt the signalling between nerve cells has now been reported by researchers in Bochum and Munich, led by Dr. Thorsten Müller from the Medizinisches Proteom-Center of the Ruhr-Universität, in the journal Molecular and Cellular Proteomics. They varied the amount of APP protein and related proteins associated with Alzheimer's disease in cell cultures, and then analysed how this manipulation affected other proteins in the cell. The result: the amount of APP present was related to the amount of an enzyme that is essential for the production of neurotransmitters and therefore for communication amongst nerve cells.

Proteomics: analysing all the proteins of the cells at once

Amyloid plaques are a characteristic feature of Alzheimer's disease. They consist largely of cleavage products of the so-called amyloid precursor protein APP, which occur in excess in the brains of Alzheimer's patients. What role APP plays in healthy people and why the abnormal accumulation of amyloid disrupts the regular functioning of the brain is still largely unclear. To understand the function of APP, the RUB researchers established a new cell model. The new cells produced only a very small amount of APP. What impact this had on all the other proteins of these cells was examined by the researchers through the use of mass spectrometry, among other things. With this method they identified over 2000 proteins and determined their concentrations. They were looking specifically for molecules whose concentrations in the newly established low-APP cells were different than in the reference cells that contained normal amounts of APP.

Abnormal protein able to curb neurotransmitter production

"One candidate has particularly caught our attention, this being the enzyme methionine adenosyltransferase II, alpha, MAT2A for short", Thorsten Müller said. Among other things, the enzyme is crucially involved in the production of neurotransmitters. Low-APP cells contained less MAT2A than the reference cells. To confirm the connection between the "Alzheimer's protein" APP and the neurotransmitter-producing MAT2A, the team studied tissue samples from the brains of deceased Alzheimer's patients and from healthy individuals. In the tissue of the Alzheimer's patients there was less MAT2A than in the healthy samples. These results suggest that APP and MAT2A concentrations are related and are linked to the synthesis of neurotransmitters. "Our results point to a new mechanism by which the defective cleavage of the APP protein in Alzheimer's disease could be directly related to altered neurotransmitter production", Müller said. "As a result, the signal transduction of nerve cells could be disrupted, which, over an extended period, could possibly also cause the death of cells."