Summary Alzheimer's disease (AD), a neurodegenerative disorder, is the leading cause of dementia. Amyloid-beta (Aβ) and tau are major contributors to AD onset and progression. Here, we investigate the therapeutic potential of CD5L, a macrophage-specific secretory protein, in reducing Aβ accumulation and improving AD pathology. CD5L directly binds to Aβ, particularly the neurotoxic Aβ42, and blocks their aggregation. Moreover, CD5L enhances microglial phagocytosis against several forms of Aβ40 and Aβ42. In 5xFAD mice, a well-established AD murine model, forced expression of CD5L reduces Aβ plaque size and number. RNA sequencing shows that CD5L promotes phagocytic activity in microglia within the 5xFAD mouse brain. Furthermore, adeno-associated virus (AAV)-mediated delivery of CD5L improves cognitive function, as demonstrated by enhanced performance in the T-maze test. These findings highlight the role of CD5L in inhibiting Aβ aggregation and facilitating Aβ clearance via enhanced phagocytosis, offering a promising therapeutic strategy for AD.
Maehara et al. (2026) studied this question.