Molecular Modeling of the Regulation of Proteins and the Treatment of Alzheimer's: Amyloid Beta and Protein Kinase C

Alzheimer’s Disease is one of the most prevalent forms of dementia that develops in elderly people with symptoms typically appearing after the age of 60.  The most major effect of the disease is loss of memory, which can leave a person unable to remember specific details or even how to perform daily tasks. The effects on the brain are likely caused by amyloid plaques and neurofibrillary tangles which cause the loss of connection between neurons in the brain. The formation of plaques and tangles occurs in people without Alzheimer’s as they age, but the amount of formation is much less than in patients with the disease and does not lead to problems with memory skills. Build-up of plaques and tangles continues with time to the point where communication between brain cells is so badly damaged that symptoms are noticeable in patients.

While a cure for Alzheimer’s Disease has not been found, various form of treatment have been developed to slow the effects on the brain. Some of the drugs used include cholinesterase, which acts as a chemical messenger in the brain for memory function, and memantine, which can regulate chemical messengers. Many other drugs are used to downplay symptoms of the disease though they do not slow the damage to nerve cells.

Protein kinase C (PKC) is a superfamily of enzymes which uses transduction of cellular signals after prolonged activation for a wide variety of cellular functions ranging from control of processes at the cellular level, such as differentiation and proliferation, up to higher-level processes including memory. Activation of PKC has been linked to learning processes in animals, supporting the idea of its role as an essential aspect in development and maintenance of memory. One of the roles of PKC-ε, a particular isoform of PKC, is the down-regulation of amyloid beta (Aβ), a peptide formed by sequential cleavages of the amyloid precursor protein (APP) (Nelson, 2009).  Aβ can form an oligomer which forms tangles on dendrites in the brain.  This could be a cause of reduced signal transmission across synapses, leading to damage of neural function, especially loss of memory. 

This work presents a molecular modeling study of the interaction of a pharmaceutical PKC-ε activator, bryostatin-1, and PKC-ε in order to identify the optimum binding site and to analyze its binding affinity to the target protein. The bryostatin-1 compound has been tested as a PKC-ε activator and shown to both decrease memory loss and increase learning ability in experiments on rats (Hongpaisan, 2007).  Bryostatin has also been tested as an antidepressant and a way to slow the growth of tumors (Sun, 2006).

Hongpaisan, J., and D. L. Alkon. "A Structural Basis for Enhancement of Long-term Associative Memory in Single Dendritic Spines Regulated by PKC." Proceedings of the National Academy of Sciences 104.49 (2007): 19571-9576.

Nelson, Thomas J., Changhai Cui, Yuan Luo, and Daniel L. Alkon. “Reduction of Beta-Amyloid Levels by Novel PKC Epsilon Activators.” Journal of Biological Chemistry 284.50 (2009): 34514-34521.

Sun, Miao-Kun, and Daniel L. Alkon. "Bryostatin-1: Pharmacology and Therapeutic Potential as a CNS Drug." CNS Drug Reviews 12.1 (2006): 1-8.