Title:Small Molecules and Alzheimer’s Disease: Misfolding, Metabolism and Imaging
VOLUME: 12 ISSUE: 5
Author(s):Viharkumar Patel, Xueli Zhang, Nicolas A. Tautiva, Akwe N. Nyabera, Opeyemi O. Owa, Melvin Baidya, Hee Chang Sung, Pardeep S. Taunk, Shahrzad Abdollahi, Stacey Charles, Rachel A. Gonnella, Nikhita Gadi, Karen T. Duong, Janelle N. Fawver, Chongzhao Ran, Tuula O. Jalonen and Ian V.J. Murray
Affiliation:Department of Physiology and Neuroscience, P.O Box 7, St. George’s University, St Georges, Grenada, West Indies.
Keywords:Alzheimer's disease, amyloid binding, animal models, ATP, brain imaging, near infrared fluorescence, small compounds.
Abstract:Small molecule interactions with amyloid proteins have had a huge impact in Alzheimer's disease (AD), especially
in three specific areas: amyloid folding, metabolism and brain imaging. Amyloid plaque amelioration or prevention
have, until recently, driven drug development, and only a few drugs have been advanced for use in AD. Amyloid proteins
undergo misfolding and oligomerization via intermediates, eventually forming protease resistant amyloid fibrils. These fibrils
accumulate to form the hallmark amyloid plaques and tangles of AD. Amyloid binding compounds can be grouped
into three categories, those that: i) prevent or reverse misfolding, ii) halt misfolding or trap intermediates, and iii) accelerate
the formation of stable and inert amyloid fibrils. Such compounds include hydralazine, glycosaminoglycans, curcumin,
beta sheet breakers, catecholamines, and ATP. The versatility of amyloid binding compounds suggests that the amyloid
structure may serve as a scaffold for the future development of sensors to detect such compounds. Metabolic dysfunction
is one of the earliest pathological features of AD. In fact, AD is often referred to as type 3 diabetes due to the presence
of insulin resistance in the brain. A recent study indicates that altering metabolism improves cognitive function.
While metabolic reprogramming is one therapeutic avenue for AD, it is more widely used in some cancer therapies. FDA
approved drugs such as metformin, dichloroacetic acid (DCA), and methylene blue can alter metabolism. These drugs can
therefore be potentially applied in alleviating metabolic dysfunction in AD. Brain imaging has made enormous strides
over the past decade, offering a new window to the mind. Recently, there has been remarkable development of compounds
that have the ability to image both types of pathological amyloids: tau and amyloid beta. We have focused on the
low cost, simple to use, near infrared fluorescence (NIRF) imaging probes for amyloid beta (Aβ), with specific attention
on recent developments to further improve contrast, specificity, and sensitivity. With advances in imaging technologies,
such fluorescent imaging probes will open new diagnostic avenues.
