Neuronal mitochondria-targeted micelles relieving oxidative stress for delayed progression of Alzheimer's disease.

Mitochondrial dysfunction is an early event of Alzheimer's disease (AD), contributes the onset and progression of AD, and may represent an effective therapeutic target for AD intervention. Since mitochondria in central neurons are more susceptible to oxidative damage than non-neuronal cells, the specific delivery of the antioxidants to the mitochondria of impaired central neurons is crucial for achieving the therapeutic effect on AD. Here, we prepare the neuronal mitochondria-targeted micelles (CT-NM) through co-decoration with neural cell adhesion molecule (NCAM) mimetic peptide C3 for brain neuron specific binding and the triphenylphosphonium (TPP) for mitochondrial targeting. CT-NM significantly increase the encapsulated resveratrol's concentration in the neuronal mitochondria compared to the micelles modified with C3 only or the resveratrol solution. The resveratrol-loaded CT-NM alleviate the oxidative stress in the neuronal cells, resulting in stabilization of the dynamic balance of mitochondrial fission and fusion. The targeted micelles restore the cognitive performance in APP/PS1 transgenic mice to the level of wild-type mice characterized by up-regulation of sirtuin 1 expression, reduction of amyloid deposition and tau hyperphosphorylation, protection of synapses and inhibition of microglia proliferation. The results demonstrate the delay of the progression of AD through reversing neuronal mitochondrial dysfunction by the targeted delivery of antioxidants.