Immune Receptor Lag3 Deletion Alleviates Neurodegeneration Phenotypes in a Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is the leading cause of dementia, but effective treatments remail unavailable. Using the 5xFAD familial AD mouse model, we show that deletion of the immune checkpoint receptor Lymphocyte activation gene 3 (Lag3) reduces amyloidosis, microgliosis, and neurodegeneration-related behavioral deficits. Transcriptional profiling revealed that Lag3 deletion reverses aberrant expression of disease-associated microglia (DAM) genes and decreased CD8+ T cells infiltration in the brain. These findings suggest that Lag3 regulates microglia function and may represent a potential therapeutic target for AD. RNA-seq was performed on FACS purified microglia isolated from hippocampal tissue of 36 mice representing four genotypes WT, 5xFAD+, Lag3-/-, and Lag3-/-; 5xFAD+. Female mice were analyzed at three ages (3-, 6-, and 9-month), with n = 3 biological replicates per group to assess genotype- and age-dependent transcriptional changes associated with Alzheimer’s disease progression and the role of Lag3 in modulating disease-associated phenotypes.