Native PLGA nanoparticles attenuate disease pathology via multiple pathways in 5xFAD Alzheimer's model

Elevated amyloid beta (Aβ) levels and aggregation contribute to neurotoxicity and development of Alzheimer's disease (AD), the leading cause of dementia in the elderly. While we reported that native poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, clinically used in drug delivery, suppress Aβ aggregation/toxicity, their effects in adult 5xFAD mice with advanced Aβ pathology remain unknown.

We evaluated the effects of native PLGA in 8-month-old male 5xFAD mice via chronic intracerebroventricular (ICV) infusion using mini osmotic pumps. Cognitive function, amyloid level/burden, synaptic integrity, and neurodegenerative events were assessed along with transcript levels in brain tissues using bulk RNA sequencing (RNA-seq).

PLGA treatment reversed cognitive deficits, reduced Aβ levels/deposits, and attenuated neurodegenerative events. These effects were associated with modulation of Aβ production, oxidative stress, and lysosomal Aβ clearance. RNA-seq revealed transcriptional changes related to vesicle trafficking, immune activity, and redox regulation.

Native PLGA, by targeting different facets of the Aβ axis, offer unique therapeutic potential in treating AD-related pathology.