A novel neuroinflammation-responsive hydrogel based on mimicking naked mole rat brain microenvironment retards neurovascular dysfunction and cognitive decline in Alzheimer’s disease

• Mimicking naked mole rat brain microenvironment is a novel strategy for AD treatment. • TM-HA-NRG1 gels could deliver naked mole rat HMM-HA and NRG1 in AD brain. • Continuous intervention obviously reduced C1q-related pathology in the AD brain. • This justifies future anti-aging cure by organism extracts of naked mole rat. Neuroinflammation is one of the major processes that trigger neuropathological amyloid-β (Aβ) deposition and contribute to Alzheimer’s disease (AD) progression. Naked mole rats, which are the longest living rodents and exhibit negligible senescence, have a special brain microenvironment characterized by high-molecular-mass hyaluronan (HMM-HA) and high levels of neuregulin 1 (NRG1), which are related to resistance to neuroinflammation and Aβ deposition, leading to protection from AD. Thus, mimicking the unique brain microenvironment of the naked mole rat as a strategy for AD treatment is of critical interest. Here, naked mole rat HMM-HA and NRG1 were used to establish an injectable neuroinflammation-responsive triglycerol monostearate (TM)-HA-NRG1 hydrogel to alter the brain microenvironment in the early to late stages of AD. Intracerebroventricular (ICV) delivery of the hydrogel resulted in significant mitigation of Aβ plaque formation and complement C1q deposition in the hippocampus. Interestingly, we found that C1q deposition on pericytes was probably associated with capillary dysfunction. Furthermore, continuous intervention obviously reduced C1q deposition on pericytes and improved the oxygen supply to the brain. Importantly, in 16-month-old AD mice, cognitive decline was significantly ameliorated after TM-HA-NRG1 hydrogel treatment. Thus, the work reported here provides a potential early intervention strategy for retarding later AD progression.