New Findings in Alzheimer’s Disease Research: The Regulatory Role of Signal Peptide Peptidase-Like 2b in the β-Amyloid Cascade

Alzheimer’s Disease (AD) is a complex neurodegenerative disorder characterized by the abnormal accumulation of β-amyloid peptides (Aβ) in brain tissue and the formation of intracellular neurofibrillary tangles. The abnormal accumulation of Aβ is considered a key factor in promoting AD pathology. With an aging population, the incidence of AD is increasing annually, posing a significant challenge to global public health and placing a heavy burden on patients and their families. Therefore, studying the pathogenesis of AD and identifying effective therapeutic targets is of great importance.

Research Background and Objectives

In traditional AD research, Aβ originates from the amyloid precursor protein (APP) via cleavage by β- and γ-secretases. γ-secretase cleaves the transmembrane region of APP, producing Aβ peptides of varying lengths, among which Aβ42 is highly neurotoxic and prone to forming β-sheet structures. Recently, immunotherapy targeting Aβ has shown some positive effects. The FDA-approved aducanumab and lecanemab significantly reduce Aβ plaques but do not markedly halt disease progression or reverse memory loss.

Thus, identifying new, more specific, and effective molecular targets to reduce Aβ levels and improve memory deficits has become a research hotspot. This paper focuses on a novel enzyme—signal peptide peptidase-like 2b (SPPL2b) and investigates its potential role in AD pathology.

Research Origin and Publication Information

This study was jointly conducted by scientists from multiple research teams, including Riccardo Maccioni, Caterina Travisan, and Jack Badman, from renowned institutions such as Karolinska Institutet, Scripps Research, and KU Leuven. The research findings were published in the February 2024 issue of the journal “Progress in Neurobiology.”

Detailed Research Process and Findings

Research Process

1. Cell Experiments and Gene Knockout: In vitro experiments used SH-SY5Y human cell lines expressing the Swedish mutant of APP and HEK293 cells with SPPL2b overexpression and knockout. Changes in SPPL2b, Bri2, and APP were assessed using Western blot and immunofluorescence techniques.
2. Mouse Model Research: Using APP Knock-In mouse models (APP^NL-G-F), the expression changes of SPPL2b were studied at different pathological stages of 3, 10, and 22 months. Brain slices and primary cell cultures were maintained to study SPPL2b expression changes in the presence of β-amyloid.
3. Human Sample Analysis: Brain tissue samples from AD patients and healthy controls were analyzed to investigate the regulation of SPPL2b and Bri2 in vivo.

Main Findings

1. Effect of β-Amyloid on SPPL2b Expression: In SH-SY5Y APP^Swe cells, SPPL2b expression significantly increased, suggesting that the presence of Aβ might upregulate SPPL2b expression. However, high doses of Aβ42 led to a downregulation of SPPL2b expression, indicating a biphasic regulation of SPPL2b by Aβ.
2. Impact of SPPL2b on APP Cleavage and Aβ Production: Overexpression of SPPL2b significantly increased APP cleavage and Aβ production, suggesting that SPPL2b might influence APP processing by regulating Bri2. Cells from SPPL2b knockout mice showed higher levels of Bri2 and reduced Aβ production, further confirming SPPL2b’s crucial role in APP processing and Aβ production.
3. Changes in SPPL2b Expression in AD Pathology: In the APP^NL-G-F mouse model, SPPL2b expression significantly increased in the early stages (3 months) but markedly decreased in late stages (10 and 22 months). This finding suggests SPPL2b’s involvement in the development of AD pathology. Further qPCR analysis indicated that changes in SPPL2b gene expression were not significant, suggesting that its protein level changes might be related to protein stability or transport.
4. Localization of SPPL2b in Neurons and Microglia: Immunofluorescence results showed that SPPL2b is primarily located in neurons and microglia near Aβ plaques, consistent with its role in AD pathology.

Research Significance and Value

This study is the first to comprehensively reveal the biphasic regulatory role of SPPL2b in AD pathology and its possible physiological mechanisms. SPPL2b is directly involved in Aβ generation and aggregation by regulating Bri2 and APP processing. In the early stages of pathology, SPPL2b upregulation might exacerbate Aβ generation, while in late stages, its downregulation might affect neuronal function. These findings provide new insights into understanding AD pathogenesis and a basis for developing new therapeutic strategies targeting SPPL2b.

Research Highlights

1. Novelty: This study is the first to systematically investigate the role of SPPL2b in AD pathology, uncovering its biphasic regulatory mechanism.
2. Methodological Diversity: The research combines a variety of methodological approaches, including cell experiments, mouse models, and human samples, to comprehensively verify SPPL2b’s regulatory role and mechanism.
3. Practical Application: SPPL2b as a potential therapeutic target offers new strategies for early intervention and treatment of AD.

Conclusion

SPPL2b’s role in AD pathology is becoming clearer, and as an effective molecular target, it has broad research and application prospects. Further exploration of SPPL2b’s interaction with AD pathology could bring new breakthroughs in AD treatment.

Through this study, scientists have not only provided a new theoretical foundation for AD research but also offered new hopes for the early diagnosis and intervention of the disease. This is undoubtedly an important milestone in the field of AD research.