Aβ Deposition: The "First Trigger" in the Pathogenesis of AD and Decoding its Molecular Mechanism

β-amyloid (Aβ) deposition is considered a key early event in the development of Alzheimer's disease (AD). Aβ is generated from amyloid precursor (APP) through sequential cleavage by β-secretase (BACE) and γ-secretase. Its monomers can further aggregate to form oligomers, fibrils, and insoluble plaques. Among them, Aβ oligomers (AβO) are considered to be the main form mediating synaptic damage and neurotoxicity. Therefore, inhibiting BACE and γ-secretase activity and reducing Aβ production has become one of the important treatment strategies for AD^[1].

Aβ deposition not only directly damages neurons but also induces abnormal hyperphosphorylation of tau protein and activates microglia. Early activated microglia clear Aβ through phagocytosis, but after long-term exposure to AβO, their clearance function is impaired, and they release pro-inflammatory factors such as IL-1β and IL-18 instead. AβO and tau can amplify inflammatory responses through the TLR2/4-NF-κB and NLRP3 inflammasome pathways, enhancing the activity of tau kinases such as GSK-3β and CDK5, thereby aggravating tau pathological changes. Therefore, regulating neuroinflammatory responses is considered an important intervention direction for slowing the progression of AD^[2].

In addition, AβO can also activate astrocytes and induce complement C3 upregulation, disrupting synaptic homeostasis and neuronal function. At the neuronal level, AβO interferes with Wnt/β-catenin signaling and activates the Fyn-mGluR5-NMDAR pathway, causing Ca²⁺ overload, leading to NMDAR-mediated excitotoxicity and impaired synaptic plasticity. Simultaneously, abnormal tau interactions with mitochondrial proteins further exacerbate energy metabolism disorders. In summary, the comprehensive regulation of key signaling pathways such as the Aβ-tau axis, inflammatory factors, Wnt/β-catenin, and NMDAR remains an important direction for the future development of AD treatment strategies^[3][4].