Research Projects - Alzheimers Amyloid Binding Therapeutic
Research interests include computational design of amyloid binding entities. Targeting monomer, dimers, and up to octomers of amyloid aggregated proteins.
Amyloid dimer with ligands bound
Just over 100 years ago Alois Alzheimer used staining techniques and described the pathology and symptoms of dementia that would come to be called Alzheimer’s Disease (AD). An increasing percentage of the world population will get AD in their lifetime with 7% of those over 65 and 40% of people over 80 years of age in industrialized countries being affected (Glass 2010, Cell). Despite decades of AD research an effective therapy let alone a vaccine has not been developed. However, the wealth of molecular information now known about the AD progression, and recent leads, raise hopes for the next decade of therapeutic development.
Multiple root causes of Alzheimer’s dementia have been proposed, which have varying levels of data behind them. The amyloid theory, for decades the most widely accepted paradigm, initially posited that the amyloid plaques kill brain cells and are the causative agent leading to Alzheimer’s dementia. In 1995 genetic links leading to Early onset Familial Alzheimer's disease (EOFAD) were found (Glass 2010, Cell). These mutations were in the presenilin gene which is a component of γ-secretase which cleaves the amyloid precursor protein (APP) releasing the amyloid peptide to the cytosol leading to the formation of amyloid plaques (Figure 1). In mouse models mutation of the presenilin gene causes Alzheimer’s like symptoms and could be alleviated through inactivation of presenilin (Clark 1995 , Nature). Multiple methods have proven efficacious in reducing amyloid plaques and some have been correlated with better cognitive outcome while others have not.
While both amyloid plaques and tau tangles are macroscopically visible phenomena that correlate with AD progression, recent research suggests they may not be the causative agent of dementia (Clark 1995 , Nature). A new model to fit available data has been put forward in which it is amyloid-β (Aβ) pre-plaque monomer or small oligomer that cause neuron death, not the larger plaque (Saura 1995 , J Neuroscience). In this model amyloid plaques could even inhibit neuron death by sequestering the deleterious cytolsolic amyloid monomers. In this light, previous researchers conclusions about amyloid plaque may be reinterpreted as correlative instead of causative. Compounds may have been measured to decreases amyloid plaques and result in delaying cognitive decline, however this could be due to decreased soluble amyloid which in turn decreased the plaques. While there is not consensus on the causative agent leading to AD neuron death and dementia, inhibiting Aβ in the cytosol has a significant track record already as a therapeutic target with mixed results.
Amyloid cleavage pathway