Amyloid-beta (Aβ) is a key player in Alzheimer's disease (AD), with dual roles in both normal and pathological conditions. Aβ is generated from the amyloid precursor protein (APP) through two pathways: the non-amyloidogenic pathway, which reduces Aβ production and has neuroprotective and anti-inflammatory effects, and the amyloidogenic pathway, which leads to Aβ accumulation and neurodegeneration. Aβ40 and Aβ42, produced via the amyloidogenic pathway, are particularly harmful, contributing to neuroinflammation, oxidative stress, and synaptic dysfunction. Understanding Aβ's multifaceted role is crucial for developing therapies targeting Aβ metabolism, aggregation, and clearance. Aβ has physiological functions, including antioxidant properties, neuroprotection, and memory consolidation. It can chelate metals, reducing oxidative damage and protecting neurons. Aβ1–42, in particular, has been shown to have antioxidant effects in cerebrospinal fluid (CSF), potentially protecting against oxidative damage in AD. Aβ also modulates synaptic plasticity, enhancing long-term potentiation (LTP) and memory consolidation. However, excessive Aβ accumulation, especially in the form of oligomers, leads to neurotoxicity, synaptic dysfunction, and neuronal damage. Aβ also influences the blood-brain barrier (BBB) and angiogenesis. It can regulate angiogenesis, with nanomolar concentrations promoting endothelial cell proliferation and micromolar concentrations inhibiting it. Aβ peptides, particularly oligomers, disrupt BBB integrity, leading to increased permeability and entry of harmful substances into the brain. Aβ interacts with various receptors, including NMDA receptors, contributing to excitotoxicity and synaptic dysfunction. Aβ's interaction with prion protein (PrP) is also significant. Aβ oligomers can bind to PrP, inhibiting NMDA-mediated synaptic transmission. PrP can inhibit BACE1, reducing Aβ production, suggesting a potential therapeutic role for PrP in AD. Aβ also interacts with glial cells, influencing neuroinflammation and Aβ dyshomeostasis. Inflammation and oxidative stress can impair Aβ clearance, leading to its accumulation and plaque formation. Aβ oligomers can disrupt microglial function, impairing their ability to clear Aβ. Overall, Aβ's dual role in AD highlights the complexity of its functions, from neuroprotection to neurotoxicity. Understanding these mechanisms is essential for developing effective therapeutic strategies targeting Aβ metabolism and clearance.Amyloid-beta (Aβ) is a key player in Alzheimer's disease (AD), with dual roles in both normal and pathological conditions. Aβ is generated from the amyloid precursor protein (APP) through two pathways: the non-amyloidogenic pathway, which reduces Aβ production and has neuroprotective and anti-inflammatory effects, and the amyloidogenic pathway, which leads to Aβ accumulation and neurodegeneration. Aβ40 and Aβ42, produced via the amyloidogenic pathway, are particularly harmful, contributing to neuroinflammation, oxidative stress, and synaptic dysfunction. Understanding Aβ's multifaceted role is crucial for developing therapies targeting Aβ metabolism, aggregation, and clearance. Aβ has physiological functions, including antioxidant properties, neuroprotection, and memory consolidation. It can chelate metals, reducing oxidative damage and protecting neurons. Aβ1–42, in particular, has been shown to have antioxidant effects in cerebrospinal fluid (CSF), potentially protecting against oxidative damage in AD. Aβ also modulates synaptic plasticity, enhancing long-term potentiation (LTP) and memory consolidation. However, excessive Aβ accumulation, especially in the form of oligomers, leads to neurotoxicity, synaptic dysfunction, and neuronal damage. Aβ also influences the blood-brain barrier (BBB) and angiogenesis. It can regulate angiogenesis, with nanomolar concentrations promoting endothelial cell proliferation and micromolar concentrations inhibiting it. Aβ peptides, particularly oligomers, disrupt BBB integrity, leading to increased permeability and entry of harmful substances into the brain. Aβ interacts with various receptors, including NMDA receptors, contributing to excitotoxicity and synaptic dysfunction. Aβ's interaction with prion protein (PrP) is also significant. Aβ oligomers can bind to PrP, inhibiting NMDA-mediated synaptic transmission. PrP can inhibit BACE1, reducing Aβ production, suggesting a potential therapeutic role for PrP in AD. Aβ also interacts with glial cells, influencing neuroinflammation and Aβ dyshomeostasis. Inflammation and oxidative stress can impair Aβ clearance, leading to its accumulation and plaque formation. Aβ oligomers can disrupt microglial function, impairing their ability to clear Aβ. Overall, Aβ's dual role in AD highlights the complexity of its functions, from neuroprotection to neurotoxicity. Understanding these mechanisms is essential for developing effective therapeutic strategies targeting Aβ metabolism and clearance.