Alzheimer’s disease (AD) is a neurodegenerative disease associated with memory dysfunction. Amyloid ß (Aß) amyloidosis is a pathological hallmark of AD, and the prevention of Aß accumulation has been proposed as a primary target for AD therapy. One of the most promising therapeutic approaches for lowering Aß is “peripheral sequestration”. This approach involves placing a small molecule that does not enter the brain and binds tightly to Aß in the periphery (i.e. blood). The compound binds the Aß in the blood and pulls out (i.e. sequesters) Aß from the brain; thus lowering the levels of brain Aß. By using small molecules that have high affinity for Aß and do not enter the brain drug discovery scientists avoid the common bottleneck of finding drugs that cross the blood-brain barrier. This should result in higher flexibility and efficiency in drug development.
Dr. Matsuoka and colleagues have found that peripheral administration of two brain impermeable, Aß-binding compounds (gelsolin and ganglioside GM1), significantly reduced the brain Aß load in a transgenic mouse model of AD. Unfortunately, these compounds are not likely to be clinically useful in humans because they are closely related to endogenous molecules and could evoke an autoimmune response. In addition, chemical modification of these compounds is extremely difficult. Therefore, novel classes of Aß-sequestration molecules are needed. In preliminary studies, Dr. Matsuoka found that two small, Aß- binding molecules originally developed as in vivo amyloid imaging PET ligands showed significant reduction of mouse brain Aß load after peripheral treatment for as little as one week. These compounds failed as amyloid imaging ligands due to their poor brain penetration. However, because they do not enter brain and bind tightly to Aß these compounds may be ideal lead compound for peripheral Aß sequestration therapy.