Small Molecules and Alzheimer’s Disease: Misfolding, Metabolism and Imaging

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.

Inhibition of β-Amyloid Aggregation by Albiflorin, Aloeemodin and Neohesperidin and their Neuroprotective Effect on Primary Hippocampal Cells Against β-Amyloid Induced Toxicity

“…β-Amyloid (Aβ) peptides i.e., Aβ 1 polyphenols, anti-oxidants and anti-inflammatory drugs, and are reported to be Aβaggregation inhibitors that provide neuroprotection. [5][6][7][8][9][10][11] While this thematic issue reported other two kinds of curcumin derivatives [12][13] and iridium complex [14] and rhodium complex [15] as effective inhibitors of Aβ aggregation.…”

Inhibitory Activity of Curcumin Derivatives Towards Metal-Free and Metal-Induced Amyloid-β Aggregation

“…One of the articles in this thematic issue by Huang and co-worker also reported one kind of Cur derivatives as effective inhibitors of Aβ aggregation [30]. Besides, a number of different types of Aβ aggregation inhibitors have been explored up to now [31], including organic small molecules [32], short peptides, nanoparticles, and metal complexes [33,34]. (Fig.…”

Tetraphenylethylene Foldamers with Double Hairpin‐Turn Linkers, TNT‐Binding Mode and Detection of Highly Diluted TNT Vapor

“…The folding of biological molecules plays a critical role in their physiological activities, such as inheritance, substrate recognition, muscle contraction, disease occurrence, transcription, and so on. To mimic the folding strategy of biological molecules and to achieve excellent folding functions beyond those of natural molecules, many artificial foldamers that can fold into complicated 3D structures have been developed .…”