Amyloid-beta-derived diffusible ligands (ADDLs) (ADDLs)

Amyloid-beta-derived diffusible ligands (ADDLs) are soluble, non-fibrillar oligomeric assemblies of the amyloid-beta peptide that are considered highly neurotoxic (Lambert et al., 1998, PNAS). Unlike insoluble amyloid plaques, ADDLs can diffuse throughout the brain parenchyma and interact with synaptic receptors, leading to the inhibition of long-term potentiation and subsequent cognitive decline (Lacor et al., 2007, J. Neurosci.). They are a primary driver of synaptic failure and neuronal loss in the early stages of Alzheimer's disease (Haass & Selkoe, 2007, Nat. Rev. Mol. Cell Biol.). Therapeutic strategies targeting ADDLs involve monoclonal antibodies, such as lecanemab and ACU193, designed to selectively bind and neutralize these oligomers or prevent their formation (Sabbagh et al., 2023, J. Prev. Alzheimers Dis.). By reducing the concentration of these toxic species, these therapies aim to preserve synaptic integrity and slow the progression of dementia (Walsh & Selkoe, 2007, J. Neurochem.). Current clinical research focuses on the high specificity of drugs to distinguish between toxic oligomers and physiologically necessary monomers (Acumen Pharmaceuticals, 2024).

Other names

Soluble amyloid-beta oligomersAβ oligomersAβOsAmyloid-beta oligomersSoluble Aβ aggregatesAmyloid-beta protofibrils

Monoclonal antibodies and small molecules target these soluble aggregates to neutralize their neurotoxic effects, prevent their binding to neuronal receptors, or facilitate their clearance from the brain via microglial phagocytosis (Sevigny et al., 2016, Nature; van Dyck et al., 2023, N. Engl. J. Med.).