This work designs a class of biocompatible PEG-chitosan@CDs hybrid nanogels by integrating nonlinear poly(ethylene glycol) (PEG), chitosan, and graphitic carbon dots (CDs) into a single nanoparticle for two-photon fl uorescence (TPF) bioimaging, pH and near-infrared (NIR) light dual-responsive drug release, and synergistic therapy. Such hybrid nanogels can be simply prepared from a one-pot surfactant-free precipitation polymerization of the PEG macromonomers complexed with chitosan and CDs in water, resulting in a semi-interpenetration of chitosan chains and an immobilization of CDs in the nonlinear PEG networks. The embedded CDs in hybrid nanogels not only serve as an excellent confocal and TPF imaging contrast agent and fl uorescent pH-sensing probe, but also enhance the loading capacity of the hybrid nanogels for hydrophobic anticancer drug. The chitosan can induce a pH-sensitive swelling/deswelling of the hybrid nanogels for pH-regulated drug release over the physiologically important range of 5.0-7.4 and surface modulation of embedded CDs to realize fl uorescent pH sensing. The thermosensitive nonlinear PEG network can promote the drug release through the local heat produced by the embedded CDs under NIR irradiation. The in vitro results indicate that the hybrid nanogels demonstrated high therapeutic effi cacy through the synergistic effect of combined chemo-photothermal treatments.

The hyperphosphorylated microtubule-associated protein tau is present in several neurodegenerative diseases, although the causal relationship remains elusive. Few mouse models used to study Alzheimer-like dementia target tau phosphorylation. We created an inducible pseudophosphorylated tau (Pathological Human Tau, PH-Tau) mouse model to study the effect of conformationally modified tau in vivo. Leaky expression resulted in two levels of PH-Tau: low basal level and higher upon induction (4% and 14% of the endogenous tau, respectively). Unexpectedly, low PH-Tau resulted in significant cognitive deficits, decrease in the number of synapses (seen by EM in the CA1 region), reduction of synaptic proteins, and localization to the nucleus. Induction of PH-Tau triggered neuronal death (60% in CA3), astrocytosis, and loss of the processes in CA1. These findings suggest, that phosphorylated tau is sufficient to induce neurodegeneration and that two different mechanisms can induce cognitive impairment depending on the levels of PH-Tau expression.

Frequency of LATE neuropathologic change across the spectrum of Alzheimer's disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts.