CD44 LINKS GLIAL ACTIVATION TO METABOLIC DYSFUNCTION IN ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is characterized by progressive cognitive decline accompanied by amyloid-β (Aβ) accumulation, neuroinflammation, and metabolic dysfunction in the brain. Increasing evidence indicates that chronic glia-mediated innate immune activation is a key driver of disease progression; however, the molecular regulators linking inflammatory activation to pathological remodeling remain incompletely understood. CD44, a transmembrane glycoprotein expressed in immune and glial cells, is upregulated in reactive astrocytes and microglia under neurodegenerative conditions, yet its functional contribution to AD-associated neuroinflammatory programs remains unclear.

Here, we investigated the role of CD44 in AD-related neuroinflammation using the 5xFAD mouse model. Genetic deletion of CD44 was combined with transcriptomic, histological, and biochemical analyses to assess its impact on glial activation and metabolic gene programs. Quantitative PCR analyses revealed that Cd44 expression was robustly induced in 5xFAD brains and that CD44 deficiency significantly reduced the expression of key inflammatory and glial activation markers. Notably, CD44 deletion selectively suppressed A1 astrocyte–associated genes while leaving A2 astrocyte markers largely unchanged. At the tissue level, CD44-deficient 5xFAD mice exhibited reduced amyloid plaque burden and attenuated microgliosis. Consistent with these findings, protein levels of GFAP and NLRP3 were decreased upon CD44 deletion.

Unbiased RNA sequencing followed by pathway analyses demonstrated coordinated downregulation of inflammatory and glial activation gene sets, accompanied by upregulation of mitochondrial oxidative phosphorylation–related pathways. Together, these findings indicate that CD44 regulates glial transcriptional programs that couple neuroinflammatory activation to metabolic remodeling in the AD brain, identifying CD44 as a key modulator of disease-associated glial states.