Developing multifunctional ligands to treat Alzheimer's disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder leading to the loss of memory and cognition. According to World Health Organization (WHO) currently there are about 24 million people worldwide with AD. With our aging population, it is estimated that the present figures on AD will more than double by 2025.

Acetylcholinesterase (AChE) inhibitors such as donepezil (Aricept®), galanthamine (Razadyne®) and rivastigmine (Exelon®) are the current mainstay of AD treatment. However, they provide only symptomatic relief. Several lines of evidence indicate that AD is a complex condition involving multiple pathways. Recent studies indicate that as AD progresses, AChE levels decline in brain whereas butyrylcholinesterase (BuChE) levels start to increase which catalyzes the degradation of the neurotransmitter acetylcholine. This mandates the need to develop agents that block both cholinesterases (AChE and BuChE).  Furthermore, in AD, AChE enzyme co-localizes with Aβ-plaques in the CNS promoting the formation of neurotoxic AChE-Aβ-peptide complex through the peripheral active site (PAS). Therefore, small molecules that bind to the peripheral site of AChE prevent the formation of neurotoxic AChE-Aβ complex. Transition metals such as Cu2+, Zn2+ and Fe3+ are implicated in neurotoxicity leading to AD and associated dementia, supporting the need to develop molecules with metal chelating ability. This calls for multiple intervention strategies to provide symptomatic relief as well as halt the disease progression where a single molecule targets multiple pathways as opposed to the traditional “one drug, one target” approach.
 

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Investigating the mechanisms of amyloid aggregation

Partially disordered proteins such as beta-amyloid, tau, alpha synuclein and prion proteins tend to aggregate into dimers, oligomers and fibrils. These various species are known to play a significant role in the pathophysiology of a number diseases such as Alzheimer's disease and Parkinson's disease to mention a few. Unfortunately, these proteins are not amenable to high resolution structure determination techniques. In our lab we develop small molecules that can bind to partially disordered proteins to understand the forces involved in protein aggregation. These investigations will assist in identifying critical polar and nonpolar regions involved in the formation of protein aggregates, dimers, oligomers and fibrils. We use a number of in vitro biochemical techniques including fluorescence measurements to monitor aggregation kinetics, computational software to understand the forces involved in aggregation/disaggregation and transmission electron microscopy to monitor aggregation morphology.

Abeta dimer and oligomer interaction

Figure 3: Binding interactions of a small molecule with beta-amyloid dimer (above) and oligomer/fibril (below)

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Column chromatography

NMR sample