Alzheimer’s Disease (AD) is a neurodegenerative disorder that is characterized by an abundance of the beta-amyloid peptide in the brain. When AD was first discovered, it was determined that beta-amyloid was produced as a result of the proteolysis of the amyloid precursor protein (APP). Aside from its role in AD, the single-pass transmembrane APP has a high expression level in the brain and tends to concentrate at the synapses of neurons. Because of this localization, it has been suggested that APP plays a role in synapse formation and potentially plasticity. However, the exact function of APP is not known. While there is currently no answer as to why APP accumulates in the brain of elderly individuals, current therapeutic approaches tend to focus on treatments that affect APP processing. Over the past few years, the structure of APP has been closely studied. From this research came the discovery that amyloid-beta production requires two cleavage steps of the APP protein. First, beta-secretases generates the C99 fragment, which releases amyloid-beta after regulation by gamma-secretase. From here, a binding domain was discovered on the C99 fragment and is predicted to bind cholesterol. The following articles go into more detail about the binding of cholesterol to the C99 binding domain of APP using an APP antibody.
beta Amyloid Antibody [NBP2-15575] - Paraffin-embedded Rat brain. APP antibody diluted at 1:500.
Cermak et al used an APP antibody in their research of how the loss of Cathepsin B and L can lead to lysosomal dysfunction and the subsequent accumulation of key Alzheimer’s proteins. Lysosomal function is very important in neurons and a lack of degradation can lead to an accumulation of toxic molecules. They found that Cathepsin B and Cathepsin L, two lysosomal proteases, control cholesterol trafficking and AD protein retrieval. In fact, inhibition of cathepsin leads to an accumulation of cholesterol. An APP antibody specific to the C-terminal fragment, C99 was used in western blot on CHO cells that were treated with Cathepsin B and L inhibitors in order to examine the effects of lysosomal dysfunction on APP. The results demonstrated that without Cathepsin B and L, the APP protein is not degraded.
Next, Li et all used a monoclonal C99 specific antibody to block APP endocytosis and alter its processing. Given that abnormal processing of the APP protein leads to beta-amyloid accumulation and subsequent AD, therapeutic approaches to suspend APP processing are of interest. To begin, western blot analysis showed that wild-type APP expression in CHO cells incubated with the monoclonal ED-C99 antibody inhibits APP cleavage. This result was determined with the use of an APP alpha specific antibody via western blot. However, the monoclonal ED-C99 antibody was generated without the FC fragment, which promotes nonspecific antibody binding. Introduction of this antibody to CHO cells resulted in inhibition of APP alpha, yet cleavage of the APP beta. What’s more, binding of the monoclonal ED-C99 antibody increased the co-localization of APP with cholesterol. Overall, these findings show potential for future treatment targets to prevent AD.
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