Functional ultrasound imaging can detect vascular changes in tau P301S mouse model of Alzheimer’s disease

Abstract

AbstractBackgroundTauopathies are neurodegenerative disorders characterized by the accumulation of abnormal tau protein leading to cognitive and/or motor dysfunction. Evidence suggests that tauopathy mouse models develop changes in blood vessel morphology, density and altered cerebral blood flow, which could be linked to cognitive deficits in Alzheimer’s Disease. Here we assess changes in neurovascular coupling in Tau P301S mouse model (MAPT P301S, PS19) using functional ultrasound (fUS) and its relationship to histological changes and cognitive deficits.MethodHemizygous (HE) P301S mice and their wild type littermates (n=20) were used in the study. fUS imaging of the brain was performed at 6 and 7 months of age, including resting state functional connectivity (RFC), somatosensory stimulation and acetazolamide challenge (ACZ, 30 mg/kg). At 7 months contextual fear conditioning (CFC) and radial arm water maze (RAWM) tests were used to assess behavioral impairments. At study end, brains were histologically assessed for microgliosis and synaptic density.ResultAt 6 months of age, fUS imaging showed differences between genotypes in all measurements. Resting state imaging showed a reduction in RFC of sensory‐motor cortex of HE animals. Chemical stimulation showed strong vascular reaction in HE mice after ACZ challenge. Somatosensory stimulation resulted in lower response in HE mice compared to WT. The fUS data at 7 months had a lower signal‐to‐noise ratio compared to 6 months, but similar trends were observed. In RAWM HE mice made less errors and displayed a trend toward increased latency in finding the platform compared to WT. The progression pattern of HE animals during CFC differed from WT counterparts. Significant increases in microgliosis by CD68 immunostaining were observed in HE mice, accompanied by a significant reduction in synapse density.ConclusionfUS is a powerful tool for functional imaging of preclinical CNS disease models. Here we confirmed vascular changes in P301S mouse model accompanied by mild decline in cognition and significant effects on neuroinflammation and synaptic density.