journal articles
IDENTIFICATION OF A CD44-DEPENDENT CONTROL OF ASTROCYTIC AUTOPHAGIC ACTIVITY IN ALZHEIMER’S DISEASE
Haiyan Wang, Ying Long, Yu Tang, Lijie Duan, Zijie Wang, Shuzhen Zhang, Yanqing Yin, Jiawei Zhou, Wenjuan Wu, Chunjiu Zhong
BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment. Despite extensive research, the precise molecular mechanisms driving AD pathogenesis remain incompletely understood. This study sought to identify robust molecular targets and cellular basis underlying AD progression.
METHODS: We performed a systematic analysis of cross-regional transcriptomic datasets from AD patients, integrating differential expression analysis across 14 Gene Expression Omnibus (GEO) datasets with cross-regional intersection mapping. Single-nucleus RNA sequencing (snRNA-seq) was employed to resolve cell-type-specific expression patterns. Furthermore, cellular communication analysis and functional enrichment of astrocyte-specific genes were conducted. The biological role of the identified candidate was validated in vitro using Aβ42 oligomer-treated primary astrocytes via siRNA-mediated knockdown and plasmid-driven overexpression, with autophagic activity assessed through LC3-II and p62 expression.
RESULTS: The transmembrane glycoprotein receptor CD44 was identified as consistently upregulated across AD-vulnerable brain regions, including the temporal cortex, frontal cortex, entorhinal cortex, and hippocampus. snRNA-seq analysis identified this upregulation primarily to astrocytes. Intercellular signaling analysis indicated that the CD44-SPP1 axis enhanced astrocyte-glial crosstalk. Functional enrichment analysis linked astrocytic CD44 to the modulation of autophagy pathways. In vitro experiments demonstrated that CD44 knockdown promoted autophagic activation (increased LC3-II and decreased p62), whereas CD44 overexpression suppressed autophagic activity.
CONCLUSION: Our findings establish CD44 as a pivotal regulator of astrocytic autophagy in AD, highlighting its potential as a novel therapeutic target.
CITATION:
Haiyan Wang ; Ying Long ; Yu Tang ; Lijie Duan ; Zijie Wang ; Shuzhen Zhang ; Yanqing Yin ; Jiawei Zhou ; Wenjuan Wu ; Chunjiu Zhong (2025): Identification of a CD44-dependent control of astrocytic autophagic activity in Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100601