As anyone who has watched Pixar’s Inside Out will tell you, our memories play an integral role in defining our identities. Alzheimer’s disease begins by stripping away memories, followed by the abilities to speak, think, and exist independently. Even after years of investigation and millions of dollars in clinical research, no drug or therapy is capable of fully arresting the ultimately fatal progression of Alzheimer’s, let alone beginning to reverse it. However, researchers in Dr. Jürgen Götz’s group at the University of Queensland have recently published findings that may point to promising new avenues for treatment.
Researchers are still trying to identify the underlying causes of Alzheimer’s, but the dominant theory holds that the disease is caused by a constellation of genetic, lifestyle, and environmental factors.1 Alzheimer’s pathology is characterized by nerve cell death through the aggregation of two types of malfunctioning proteins.2 Specifically, an important brain protein known as amyloid-beta (Abeta) clusters into structures called plaques, and another critical brain protein known as tau weaves into groups called tangles. Tangles disrupt nerve cells’ internal transport systems, while plaques block cell-to-cell signaling and cause dangerous inflammation.3 The resulting nerve cell death, along with shortages in the vital neurotransmitter acetylcholine, causes the cognitive decline associated with Alzheimer’s.
Most FDA-approved Alzheimer’s drugs focus on increasing the amount of depleted neurotransmitters in the damaged brain.4 Unfortunately, these treatments are not always effective. Instead of targeting neurotransmitters, Dr. Götz’s team targeted Abeta protein plaques in mice using a technique called repeated scanning ultrasound (SUS) to temporarily open the blood-brain barrier (BBB).5 The BBB is the network of selectively porous capillaries that protects the brain from harmful substances.6 To open it, researchers injected the mice with microbubbles (small polymer shells with gas cores) and then exposed them to focused ultrasound pulses. The microbubbles began to expand and contract through a process known as acoustic cavitation, temporarily disrupting the protective BBB. You’re probably thinking, “Hey wait, opening this barrier up sounds pretty dangerous.” Well, you’re right. However, the benefits in this case were significant. After four weeks of SUS treatment, a statistically significant number of Abeta plaque-afflicted mice exhibited improved cognitive performance and memory. Overall, the average number plaques per brain section fell by a whopping 52%.
The researchers believe that the SUS treatment, in opening the BBB, somehow enhances the function of the brain’s microglia. Microglia are macrophages (read: the dump trucks of the immune system) that consume cellular waste.7 SUS treatment doubled the amount of Abeta plaques destroyed by microglia, leading to the observed improvements in cognition and memory. The researchers weren’t able to definitively identify why disrupting the BBB prompted microglial activation, but they found preliminary results indicating that albumin, a normally blood-borne protein previously shown to inhibit Abeta aggregation, entered the brain and produced the enhanced microglial activity.
While this study is certainly a step forward, the researchers acknowledge that there is still work to be done before human trials. Ultrasound machines capable of safely penetrating the human skull and brain must be developed, and the SUS treatment must be tested in more complex cases. Fortunately, other treatments are already in development. Solanezumab, a promising antibody-based treatment for early stages of Alzheimer’s, is currently in late-stage large-scale clinical trials.8 Those who know someone affected by Alzheimer’s can take comfort in the hope that the disease may very soon be nothing more than a forgotten memory.
Tejus Satish is a sophomore from McMurtry College at Rice University.
Alzheimer’s Disease Fact Sheet. National Institutes of Health. https://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-fact-sheet (accessed June 30, 2015)
Alzheimer’s Disease. Cleveland Clinic Center for Continuing Education. http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/alzheimers-disease/ (accessed June 30, 2015)
Alzheimer’s Basics: Plaques and Tangles. Alzheimer’s Association, Northern California and Northern Nevada Chapter. http://www.alz.org/about_us_about_us_.asp (accessed July 27, 2015)
About Alzheimer’s Disease: Treatment. National Institutes of Health. https://www.nia.nih.gov/alzheimers/topics/treatment (accessed June 30, 2015)
Leinenga, G. and Götz, H. Scanning ultrasound removes amyloid-β and restores memory in Alzheimer’s disease mouse model. Sci. Trans. Med [Online]. 2015, 278, 278-311. http://stm.sciencemag.org.ezproxy.rice.edu/content/7/278/278ra33.full (accessed June 30, 2015)
Blood-brain barrier. Merriam-Webster Online. http://www.merriam-webster.com/dictionary/blood-brain%20barrier (accessed June 30, 2015)
Microglia. Encylopædia Britannica Online. http://www.britannica.com/science/microglia (accessed June 30, 2015)
Data Using New Delayed-Start Methodology Suggested Benefit of Early Treatment with Solanezumab in Patients with Mild Alzheimer's Disease. Eli Lilly and Company. https://investor.lilly.com/releasedetail.cfm?ReleaseID=923179 (accessed July 27, 2015)