The neurotoxicity of amyloid β-protein (Aβ) is a complex process involving multiple molecular mechanisms that lead to synaptic and network dysfunction, contributing to Alzheimer's disease (AD). Aβ accumulates in brain regions critical for memory and cognition, and its toxic effects are mediated by various forms, including monomers, oligomers, and fibrils. While amyloid plaques are often considered the primary target, recent evidence suggests that soluble oligomers, which are in dynamic equilibrium with fibrils, are more neurotoxic. These oligomers can bind to various components of neuronal and non-neuronal plasma membranes, leading to synaptic dysfunction and network disorganization. Aβ oligomers are implicated in the early stages of AD, causing synaptic and cognitive impairments before the formation of amyloid plaques. These impairments are associated with altered synaptic transmission, including enhanced synaptic depression and reduced presynaptic efficacy. Aβ can also act as a positive regulator of presynaptic function, increasing the release probability of synaptic vesicles. However, at higher concentrations, Aβ can induce long-term depression (LTD) and impair synaptic plasticity, leading to cognitive deficits. The mechanisms by which Aβ exerts its neurotoxic effects involve interactions with various receptors, including α7 nicotinic acetylcholine receptors, NMDA and AMPA receptors, and others. These interactions can lead to downstream signaling cascades that contribute to neuronal dysfunction. Additionally, Aβ can disrupt membrane lipids, leading to structural changes that may contribute to its neurotoxicity. The role of Aβ in AD is further complicated by its interactions with other pathological factors, such as tau protein. While Aβ is primarily associated with synaptic dysfunction, its accumulation can also lead to neuronal loss and cognitive decline. Therapeutic strategies targeting Aβ production or removal are being explored, as well as interventions that enhance the brain's resistance to Aβ toxicity, such as reducing tau levels or modulating other copathogenic factors. Overall, the complex interplay between Aβ and various cellular and network mechanisms underscores the need for a multifaceted approach to understanding and treating AD. Understanding the precise mechanisms by which Aβ exerts its neurotoxic effects is crucial for developing effective therapies that can slow or prevent the progression of the disease.The neurotoxicity of amyloid β-protein (Aβ) is a complex process involving multiple molecular mechanisms that lead to synaptic and network dysfunction, contributing to Alzheimer's disease (AD). Aβ accumulates in brain regions critical for memory and cognition, and its toxic effects are mediated by various forms, including monomers, oligomers, and fibrils. While amyloid plaques are often considered the primary target, recent evidence suggests that soluble oligomers, which are in dynamic equilibrium with fibrils, are more neurotoxic. These oligomers can bind to various components of neuronal and non-neuronal plasma membranes, leading to synaptic dysfunction and network disorganization. Aβ oligomers are implicated in the early stages of AD, causing synaptic and cognitive impairments before the formation of amyloid plaques. These impairments are associated with altered synaptic transmission, including enhanced synaptic depression and reduced presynaptic efficacy. Aβ can also act as a positive regulator of presynaptic function, increasing the release probability of synaptic vesicles. However, at higher concentrations, Aβ can induce long-term depression (LTD) and impair synaptic plasticity, leading to cognitive deficits. The mechanisms by which Aβ exerts its neurotoxic effects involve interactions with various receptors, including α7 nicotinic acetylcholine receptors, NMDA and AMPA receptors, and others. These interactions can lead to downstream signaling cascades that contribute to neuronal dysfunction. Additionally, Aβ can disrupt membrane lipids, leading to structural changes that may contribute to its neurotoxicity. The role of Aβ in AD is further complicated by its interactions with other pathological factors, such as tau protein. While Aβ is primarily associated with synaptic dysfunction, its accumulation can also lead to neuronal loss and cognitive decline. Therapeutic strategies targeting Aβ production or removal are being explored, as well as interventions that enhance the brain's resistance to Aβ toxicity, such as reducing tau levels or modulating other copathogenic factors. Overall, the complex interplay between Aβ and various cellular and network mechanisms underscores the need for a multifaceted approach to understanding and treating AD. Understanding the precise mechanisms by which Aβ exerts its neurotoxic effects is crucial for developing effective therapies that can slow or prevent the progression of the disease.