LITHIATED GOLD NANOPARTICLES AS A PROMISING THERAPEUTIC STRATEGY FOR ALZHEIMER'S DISEASE TREATMENT

Aberrant hyperactivation of glycogen synthase kinase-3β (GSK-3β) plays a key role in Alzheimer’s disease (AD), promoting tau hyperphosphorylation and amyloid-β production. GSK-3β also mediates entry and replication of Herpes simplex virus type-1 (HSV-1), a recognized risk factor for AD when it reaches the brain. Although lithium is the most potent GSK-3β inhibitor, its systemic toxicity limits its therapeutic use in AD. We therefore developed a nanotool for intracellular lithium delivery based on glutathione-functionalized gold nanoparticles (LiG-AuNPs), enabling brain-targeted GSK-3β inhibition following intranasal administration at lithium concentrations ineffective when delivered as conventional salts.
We aimed to evaluate the therapeutic potential of LiG-AuNP treatment in counteracting the AD-like phenotype in both genetic (3xTg-AD) and sporadic (HSV-1-induced) mouse models, using behavioral, electrophysiological, and molecular approaches.
In 3xTg-AD mice, LiG-AuNPs administered intranasally for 2 months (from 12 to 14 months of age) significantly improved memory, assessed by the novel object recognition test (preference index from 48.6±1.7% to 65.9±1.6%), while reducing tau load. Five months of LiG-AuNP treatment also preserved memory in HSV-1–infected mice exhibiting an AD-like phenotype. This effect was associated with increased hippocampal Synapsin-1 expression (+55% vs. HSV-1) and a reduced pTau/Tau ratio. Accordingly, long-term potentiation at the CA3-CA1 synapse, typically impaired in AD models, was preserved by LiG-AuNP treatment (+114% vs. HSV-1).
Notably, LiG-AuNP-treated mice showed no alterations in general health status, no increase in plasma lithium levels, and no gliosis.
Collectively, these findings identify LiG-AuNPs as a promising and safe strategy for brain-targeted lithium-based therapy in AD.