Amyloid Beta (Aβ) Species in Alzheimer’s Disease
In Alzheimer’s patients, five dominant pools of Aβ species have been identified: Aβ monomers, Aβ oligomers (AβOs), protofibrils, fibrils, and amyloid plaques.1
Historically, the primary focus of Alzheimer’s drug development efforts has been on Aβ monomers and amyloid plaques.2,3
Focusing on Toxic AβOs
Acumen’s therapeutic target for Alzheimer’s disease is different from historical approaches.
Decades of research support the hypothesis that soluble AβOs are the most toxic form of Aβ. AβOs are an early trigger and persistent driver of Alzheimer’s-associated pathology and neurodegeneration.1,2,4
The accumulation of AβOs disrupts brain circuitry, preventing neurons from signaling properly, and is associated with synapse deterioration, tau hyper-phosphorylation, and inflammation.1,4
Targeting Toxic AβOs with ACU193
Recent studies suggest that eliminating the toxic soluble species from the neuronal system may enable damaged circuits to regain some of their function.3
Enter ACU193, an anti-AβO monoclonal antibody (mAb) developed to selectively target and inhibit toxic soluble AβOs, preventing them from binding to synapses, and thereby preserving or restoring neuronal function. This mechanism of action gives ACU193 the potential to be the best-in-class treatment, providing superior efficacy and safety.1,3
ACU193: The First Immunotherapy Drug Candidate Targeting Toxic Soluble AβOs
ACU193 is a monoclonal antibody that is distinguished from other anti-Aβ mAbs for several reasons:
- Highly selective for soluble oligomers, the toxic Aβ species; other anti-Aβ mAbs are less selective and/or target different amyloid species, such as monomers, fibrils, or plaques1,2,4
- Designed to provide improved clinical efficacy with lower rate of ARIA (amyloid-related imaging abnormalities) as compared to anti-plaque mAbs1,2
- Potential for cognitive improvement in addition to slowing of disease progression2
- Prevents toxic soluble AβOs from binding to synapses, thereby preserving or resorting neuronal function2
- Siemers, E., Hitchcock, J., Sundell, K. et al. ACU193, a Monoclonal Antibody that Selectively Binds Soluble Aβ Oligomers: Development Rationale, Phase 1 Trial Design, and Clinical Development Plan. J Prev Alzheimer’s Dis (2022).
- Krafft GA, Jerecic J, Siemers E and Cline EN (2022) ACU193: An Immunotherapeutic Poised to Test the Amyloid β Oligomer Hypothesis of Alzheimer’s Disease. Front. Neurosci. 16:848215.
- Goure, W. F., Krafft, G. A., Jerecic, J., & Hefti, F. (2014). Targeting the proper amyloid-beta neuronal toxins: a path forward for Alzheimer’s disease immunotherapeutics. Alzheimer’s Research & Therapy, 6(4), 42.
- Wang, X., Kastanenka, K. V., Arbel-Ornath, M., Commins, C., Kuzuya, A., Lariviere, A. J., Krafft, G. A., Hefti, F., Jerecic, J., & Bacskai, B. J. (2018). An acute functional screen identifies an effective antibody targeting amyloid-β oligomers based on calcium imaging. Scientific Reports, 8(1), 4634.
- Yang, T., O’Malley, T. T., Kanmert, D., Jerecic, J., Zieske, L. R., Zetterberg, H., Hyman, B. T., Walsh, D. M., & Selkoe, D. J. (2015). A highly sensitive novel immunoassay specifically detects low levels of soluble Aβ oligomers in human cerebrospinal fluid. Alzheimer’s Research & Therapy, 7(1), 14.
- Savage, M. J., Kalinina, J., Wolfe, A., Tugusheva, K., Korn, R., Cash-Mason, T., Maxwell, J. W., Hatcher, N. G., Haugabook, S. J., Wu, G., Howell, B. J., Renger, J. J., Shughrue, P. J., & McCampbell, A. (2014). A sensitive aβ oligomer assay discriminates Alzheimer’s and aged control cerebrospinal fluid. The Journal of Neuroscience, 34(8), 2884–2897.
- Gaspar, R. C., Villarreal, S. A., Bowles, N., Hepler, R. W., Joyce, J. G., & Shughrue, P. J. (2010). Oligomers of beta-amyloid are sequestered into and seed new plaques in the brains of an AD mouse model. Experimental Neurology, 223(2), 394–400.
- Hepler, R. W., Grimm, K. M., Nahas, D. D., Breese, R., Dodson, E. C., Acton, P., Keller, P. M., Yeager, M., Wang, H., Shughrue, P., Kinney, G., & Joyce, J. G. (2006). Solution state characterization of amyloid beta-derived diffusible ligands. Biochemistry, 45(51), 15157–15167.
- Lacor, P. N., Buniel, M. C., Chang, L., Fernandez, S. J., Gong, Y., Viola, K. L., Lambert, M. P., Velasco, P. T., Bigio, E. H., Finch, C. E., Krafft, G. A., & Klein, W. L. (2004). Synaptic targeting by Alzheimer’s-related amyloid beta oligomers. The Journal of Neuroscience, 24(45), 10191–10200.
- Gong, Y., Chang, L., Viola, K. L., Lacor, P. N., Lambert, M. P., Finch, C. E., Krafft, G. A., & Klein, W. L. (2003). Alzheimer’s disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proceedings of the National Academy of Sciences of the United States of America, 100(18), 10417–10422.
- Hefti, F., Goure, W. F., Jerecic, J., Iverson, K. S., Walicke, P. A., & Krafft, G. A. (2013). The case for soluble Aβ oligomers as a drug target in Alzheimer’s disease. Trends in Pharmacological Sciences, 34(5), 261–266.
- Rammes, G., Hasenjäger, A., Sroka-Saidi, K., Deussing, J. M., & Parsons, C. G. (2011). Therapeutic significance of NR2B-containing NMDA receptors and mGluR5 metabotropic glutamate receptors in mediating the synaptotoxic effects of β-amyloid oligomers on long-term potentiation (LTP) in murine hippocampal slices. Neuropharmacology, 60(6), 982–990.
- Shughrue, P. J., Acton, P. J., Breese, R. S., Zhao, W. Q., Chen-Dodson, E., Hepler, R. W., Wolfe, A. L., Matthews, M., Heidecker, G. J., Joyce, J. G., Villarreal, S. A., & Kinney, G. G. (2010). Anti-ADDL antibodies differentially block oligomer binding to hippocampal neurons. Neurobiology of Aging, 31(2), 189–202.