Imaging the therapeutic effects of cerebral endothelial cell derived exosome treatment of a preclinical model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is characterized by the excessive accumulation of select proteins in the brain, associated with altered vascular function, glymphatic transport, cerebrospinal fluid (CSF) dynamics, and cerebral microstructure. Exosomes derived from cerebral endothelial cells (CEC-Exo) have been demonstrated to reduce vascular dysfunction, which may beneficially impact perivascular glymphatic clearance, and potentially, protein aggregates and the corresponding microstructural disruption. METHODS: We investigated the effect of CEC-Exo therapy on AD by assessing glymphatic transport, CSF motion, and microstructural integrity using magnetic resonance imaging (MRI), and measuring cognitive performance. TgF344-AD rats, at 12-months of age, were randomly treated with CEC-Exo (1×1011 particles/intravenous injection) or saline twice-weekly for four consecutive weeks. MRI measurements, including dynamic 3D T1-weighted imaging with contrast agent and diffusion MRI (dMRI) with multiple b-values, were conducted for all rats at 13-months. Glymphatic function was evaluated with tracer-induced time signal curve (TSC), while microstructural state and CSF motion were assessed with parameters derived from dMRI acquired at high (dMRIhigh-b) and low (dMRIlow-b) b-values, respectively. Cognitive performance was assessed by the Morris water maze (MWM) test. RESULTS: TSCs demonstrated significantly higher peak values in the olfactory bulb and whole brain in the CEC-Exo-treated group than in the saline-treated group. With the CEC-Exo treatment, a significantly increased MDlow-b, a measure of pseudorandom CSF motion derived from dMRIlow-b, was observed in the representative CSF-filled space. As revealed by dMRIhigh-b-derived parameters, CEC-Exo treatment resulted in significantly elevated axonal water fraction, fractional anisotropy, and Kurtosis in white matter, as well as significantly reduced mean diffusivity, axial diffusivity, and radial diffusivity in both white and gray matter in the AD brain. In the MWM test, CEC-Exo-treated rats spent a significantly greater percentage of time in the correct quadrant than did saline-treated rats. CONCLUSION: CEC-Exo treatment preserved glymphatic transport, CSF motion, and microstructural integrity in the AD brain, accompanied by a reduced cognitive decline. With a global therapeutic impact, the CEC-Exo therapy provides a novel strategy on the treatment of AD. Our data support the value of dMRIlow-b as a clinically feasible imaging tool for assessing alterations in CSF dynamics that mediate perivascular glymphatic clearance.