Alzheimer's disease (AD) is a neurodegenerative disorder linked to protein misfolding and aggregation. AD is pathologically characterized by senile plaques formed by extracellular Amyloid-β (Aβ) peptide and Intracellular Neurofibrillary Tangles (NFT) formed by hyperphosphorylated tau protein. Extensive synaptic loss and neuronal degeneration are responsible for memory impairment, cognitive decline and behavioral dysfunctions typical of AD. Amyloidosis has been implicated in the depression of acetylcholine synthesis and release, overactivation of N-methyl-D-aspartate (NMDA) receptors and increased intracellular calcium levels that result in excitotoxic neuronal degeneration. Current drugs used in AD treatment are either cholinesterase inhibitors or NMDA receptor antagonists; however, they provide only symptomatic relief and do not alter the progression of the disease. Aβ is the product of Amyloid Precursor Protein (APP) processing after successive cleavage by β- and γ-secretases while APP proteolysis by α-secretase results in non-amyloidogenic products. According to the amyloid cascade hypothesis, Aβ dyshomeostasis results in the accumulation and aggregation of Aβ into soluble oligomers and insoluble fibrils. The former are synaptotoxic and can induce tau hyperphosphorylation while the latter deposit in senile plaques and elicit proinflammatory responses, contributing to oxidative stress, neuronal degeneration and neuroinflammation. Aβ-protein-targeted therapeutic strategies are thus a promising disease-modifying approach for the treatment and prevention of AD. This review summarizes recent findings on Aβ-protein targeted AD drugs, including β-secretase inhibitors, γ-secretase inhibitors and modulators, α-secretase activators, direct inhibitors of Aβ aggregation and immunotherapy targeting Aβ, focusing mainly on those currently under clinical trials.

中文翻译：

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针对阿尔茨海默氏病的β-淀粉样蛋白的治疗策略。

阿尔茨海默氏病（AD）是一种与蛋白质错误折叠和聚集有关的神经退行性疾病。AD的病理特征是由细胞外淀粉样蛋白（Aβ）肽形成的老年斑和由高磷酸化tau蛋白形成的细胞内神经原纤维缠结（NFT）。广泛的突触损失和神经元变性是AD的典型记忆障碍，认知能力下降和行为障碍的原因。淀粉样变性病与乙酰胆碱合成和释放的降低，N-甲基-D-天冬氨酸（NMDA）受体的过度活化以及细胞内钙水平升高有关，导致兴奋性神经毒性。目前用于AD治疗的药物是胆碱酯酶抑制剂或NMDA受体拮抗剂。然而，它们仅提供症状缓解，不会改变疾病的进程。Aβ是β-和γ-分泌酶连续切割后淀粉样前体蛋白（APP）加工的产物，而α-分泌酶进行APP水解则产生非淀粉样产物。根据淀粉样蛋白级联假说，Aβ异位稳态导致Aβ聚集和聚集为可溶性低聚物和不溶性原纤维。前者具有突触毒性，可诱导tau过度磷酸化，而后者则沉积在老年斑中并引起促炎反应，从而导致氧化应激，神经元变性和神经炎症。因此，以Aβ蛋白为靶点的治疗策略是用于治疗和预防AD的有希望的疾病缓解方法。