Novel Approaches to Drug Development for Alzheimer's Disease

What is it about?

Alzheimer’s disease (AD) is a deteriorating neurodegenerative non-curable disease that affects millions worldwide. Current drugs have side effects that are significant. In AD, the beta-amyloid precursor protein (APP), critical for normal neuron growth, survival and repair, is improperly cleaved by specific aspartic proteases creating fragments that form amyloid beta. These fragments aggregate outside neurons and create plaques which lead to destruction of neural signaling. The pathophysiology of AD is complex and there are many approaches to combatting the disease. In this review a structural search was done in the Protein Data Bank (PDB) for all protein targets in the absence and presence of inhibitors and regulating molecules involved in AD. In addition, preliminary characterization (sizing) of nanoparticles with fluorescent spectroscopy and dynamic light scattering is reported. Structural examples analyzed include Presenilin Homologue (PSH) protein and Mint1 which are important for the regulation of APP. Mint1 and Presenilin are examples analyzed of the phosphotyrosine-binding (PTB) domain. Recent studies of the inhibition of the aspartic protease BACE1 that is known to cleave APP to beta amyloid essential to forming beta amyloid plaques is reviewed. A structural analysis of BACE1/inhibitor complexes is provided with suggested modifications to increase bioavailability of inhibitors. Finally, a novel technique utilizing nanoparticles to destroy beta-amyloid plaques is introduced as a possible future therapy for AD.

Featured Image

Why is it important?

The review is focused on structural analysis of various protein targets relevant to Alzheimer's Disease (AD). The work is significant because the focus is novel: A survey of current known three dimensional protein structures in the Rutgers Consortium of Structural Biology (RCSB) Protein Data Bank (PDB) relevant to AD are analyzed.

Perspectives