The study investigates the neurotoxic effects of Aβ1-42-derived diffusible ligands (ADDLs), which are small, nonfibrillar oligomers of Aβ1-42. These ADDLs are formed under conditions that inhibit fibril formation and are highly toxic to mature neurons in organotypic central nervous system (CNS) cultures at nanomolar concentrations. ADDLs bind to trypsin-sensitive sites on cell surfaces, and tryptic peptides derived from these sites block ADDL binding and toxicity. The toxicity of ADDLs is dependent on the presence of Fyn, a protein tyrosine kinase linked to apoptosis and elevated in Alzheimer's disease. Notably, neurological dysfunction caused by ADDLs occurs before cellular degeneration, and they inhibit hippocampal long-term potentiation (LTP) without causing cell death. The findings suggest that early memory loss and subsequent dementia in Alzheimer's disease may be caused by the biphasic impact of ADDLs on synaptic plasticity and signal transduction pathways.The study investigates the neurotoxic effects of Aβ1-42-derived diffusible ligands (ADDLs), which are small, nonfibrillar oligomers of Aβ1-42. These ADDLs are formed under conditions that inhibit fibril formation and are highly toxic to mature neurons in organotypic central nervous system (CNS) cultures at nanomolar concentrations. ADDLs bind to trypsin-sensitive sites on cell surfaces, and tryptic peptides derived from these sites block ADDL binding and toxicity. The toxicity of ADDLs is dependent on the presence of Fyn, a protein tyrosine kinase linked to apoptosis and elevated in Alzheimer's disease. Notably, neurological dysfunction caused by ADDLs occurs before cellular degeneration, and they inhibit hippocampal long-term potentiation (LTP) without causing cell death. The findings suggest that early memory loss and subsequent dementia in Alzheimer's disease may be caused by the biphasic impact of ADDLs on synaptic plasticity and signal transduction pathways.