Alzheimer's Disease (AD) is the most common type of dementia in the elderly, which is characterized by progressive cognitive dysfunction (Alzheimers Dement., 2022; Alzheimers Dement., 2023; Chen et al., 2023). The etiology of AD remains unclear, involving a variety of complex factor (Larsson et al., 2017; Scheltens et al., 2021; Cai et al., 2023). However, β-Amyloid (Aβ) is still considered a core pathogenic substance in AD (Selkoe and Hardy, 2016). Reducing the Aβ burden in the brain is an important approach for treating AD.

Apoptosis-associated speck-like protein containing a CARD (ASC) is a key protein that initiates immune-inflammatory responses. It consists of an N-terminal pyrin domain (PYD) and a C-terminal caspase recruitment domain (CARD), existing in an unstructured conformation, and plays an important regulatory role in Aβ aggregation and deposition. Aβ deposition in AD activates innate immune cells to release ASC, forming ASC speckles (Venegas et al., 2017; Rathinam and Chan, 2018). Aβ aggregates around ASC protofibrils to enhance their toxicity (Friker et al., 2020; de Souza et al., 2021). ASC speckles and chemotactic Aβ cross-seeding promote Aβ oligomerization and aggregation (Lučiūnaitė et al., 2020; Stancu et al., 2019). The NLRP3 inflammasome acts as a key mediator of AD pathology. Upon activation by Aβ, it releases extracellular ASC specks that cross-seed Aβ deposition and propagate neuroinflammation (Heneka et al., 2013, Venegas et al., 2017)[8, 23254930]. Thus, neutralizing ASC signaling offers a potential avenue to disrupt this pathogenic cycle.Studies have shown that intraperitoneal injection of a humanized antibody to ASC reduced the inflammatory factor levels in mice cortex (Desu et al., 2020). The anti-ASC antibody blocked the ASC-induced Aβ aggregation, attenuating inflammation in AD mice (de Rivero Vaccari et al., 2009). However, exogenous antibodies have limited clinical application due to difficulties crossing the blood-brain barrier or their toxic side effects.

Recent studies have further elucidated the complex interplay between innate immunity, metabolic dysregulation, and neurodegeneration in AD pathogenesis (Ren et al., 2025; Wei et al., 2024).Although monoclonal antibodies targeting Aβ have shown promise in reducing plaque burden, their clinical efficacy, safety profile, and accessibility remain controversial, highlighting the urgent need for alternative or complementary therapeutic strategies (Yin et al., 2026).Immunotherapy is currently one of the important strategies in the treatment of AD20. Naturally occurring autobodies (NAbs) are widespread in human blood (Liu et al., 2021; Jian et al., 2022a; Gu et al., 2023). The destruction of the blood-brain barrier and increased permeability lead to autoantibody disorders in AD (DeMarshall et al., 2016). Naturally occurring antibodies against ASC (NAbs-ASC) exist in blood (de Rivero Vaccari et al., 2009). However, the profiles and pathophysiological significance of NAbs-ASC in the pathogenesis of AD remain undetermined.

However, whether NAbs-ASC levels are altered in AD and whether they could be harnessed for therapeutic purposes remain to be established. Therefore, the objectives of this study were to: (1) examine plasma NAbs-ASC levels in AD patients and assess their correlation with cognitive function and Aβ biomarkers; (2) investigate the effects of NAbs-ASC on Aβ production and cytotoxicity in vitro; and (3) evaluate the therapeutic potential of both passive immunotherapy (NAbs-ASC administration) and active immunotherapy (ASC peptide immunization) in APP/PS1 mice.