UCLA researchers from the Department of Neurology have developed a novel application of two compounds that target the upstream formation of toxic amyloid-beta oligomers for the effective treatment of Alzheimer’s disease.
BACKGROUND: Alzheimer’s Disease (AD) is the most common age-related neurodegenerative disorder currently affecting ~6 million people in the U.S. By 2050, it is projected that AD will affect ~14 million Americans, making this disease a growing national crisis. Progression of AD is irreversible and leads to degeneration of memory and thinking skills. Underlying these neurodegenerative symptoms, lies physiological changes in brain tissue due to the accumulation of amyloid plaques (or toxic oligomers) largely comprised of amyloid-B (AB) and neurofibrillary tangles of hyperphosphorylated tau protein. In healthy brains, AB normally functions as a monomer that serves to carry out essential jobs in brain cells. However, when AB collects into oligomers, as in AD, accumulation leads to toxic effects. The toxic oligomers stem from full-length Amyloid Precursor Protein (APP) that are normally broken in healthy brains by a series of proteases. It is believed that these proteases are deregulated in AD progression, along with an upregulation of a secretase known as BACE1. While many clinical trials have targeted inhibition of amyloid-β product or have attempted to increase the clearance of amyloid plaques, no current treatment is effective in eliminating AD progression. Instead, much recent research has been devoted to the effects that the upregulation of natural inhibitors to secretases like BACE1 have in AD progression. Preliminary research has suggested that the upstream targeting of AB oligomer formation, may be an effective method to slowing or eliminating the progression of AD: though there are no current therapeutics targeting this pathway on the market. Considering the crisis of a growing population with AD progression, there exists a crucial need for the development of an effective treatment strategy for AD.
INNOVATION: UCLA researchers from the Department of Neurology have developed a novel application of two compounds that target the upstream formation of toxic amyloid-beta oligomers for the effective treatment of Alzheimer’s disease. The treatment strategy targets sAPPα which acts as an endogenous inhibitor to BACE1. Additionally, sAPPα is a trophic enhancer, that increases synaptic plasticity and maintains neuronal function: meaning that its upregulation may lead to reversal in the degeneration of thinking and memory skills. The researchers identified two compounds that significantly upregulate sAPPα in CHO-7W (>25%) and human neuroblastoma SH-SY5Y cells (p < 0.01) through high-throughput screening. The mechanism underlying the upregulation of sAPPα was then elucidated through a potentially novel mechanism involving the neuronally-expressed protein reticulon-3 (RTN3). RTN3 is a highly neuronally-expressed reticulon protein, and RTN3 monomers have been shown to negatively regulate BACE1. The use of these identified compounds, serve as a novel and promising treatment pathway in the progression of AD.
POTENTIAL APPLICATIONS:
• The treatment of AD
• Direct inhibition of BACE1
• Increased plasticity and preservation of neuronal function to reverse neurodegeneration caused by AD
ADVANTAGES:
• Novel mechanism-of-action to enhance sAPPα, that work upstream of AB formation
• No current commercial treatment exists to target AD progression upstream of AB plaque formation
DEVELOPMENT-TO-DATE:
A high-throughput screen utilizing the UCLA small molecule library was completed in Chinese Hamster ovary cells stably expressing human amyloid precursor protein. Briefly, CHO-7W cells (5k/well) were treated with 5 uM compounds for 48 hours followed by the collection of media and determination of sAPPα levels by AlphaLISA. The results were validated and confirmed in human neuroblastoma SH-SY5Y cells. Global proteomic analysis of drug-treated neurons revealed Remacemide’s novel mechanism-of-action.
Related Papers (from the inventors only)
Libeu, C. A. P., Descamps, O., Zhang, Q., John, V. & Bredesen, D. E. Altering APP proteolysis: increasing sAPPalpha production by targeting dimerization of the APP ectodomain. PLoS One 7, e40027 (2012).