Multiple courses of BBB opening with pulsed Focused Ultrasound and Microbubbles promotes phosphorylated Tau production

Authors

• ZI Kovacs
• TW Tu
• M Sundby
• BK Lewis
• SR Burks
• JA Frank

Abstract

Blood-brain barrier (BBB) opening with pulsed Focused Ultrasound and Microbubbles (pFUS+MB) has been proposed as a novel strategy for Alzheimer’s disease therapeutics either by reducing the number of amyloid plaques. The goal of this study was to investigate the impact of multiple courses of BBB opening with pFUS+MB on potential phosphorylated Tau (pTau) production. Female rats (n=6) received either a single or 6 weekly pFUS+MB in the cortex and the contralateral hippocampus. MRI T2, T2* and Gd-enhanced T1-weighted images were obtained. Histological evaluation for microglia and astrocytes, neurogenesis, microhemorrhage and pTau was performed. Statistical analysis was performed comparing sonicated to contralateral brain. After each sonication GdT1 MRI demonstrated BBB disruption in the C and the H. T2* MRI showed hypointensities indicative of metallophagocytic cells and ferritin accumulation in both treated regions associated with brain atrophy. Histological evaluation showed astrocyte and microglia activation, and the increase in BrdU+ cells. pTau positive neurons occurred following multiple weekly courses of pFUS+MB. Weekly pFUS+MB exposures resulted in morphological and pathological changes that demonstrated evidence of vascular damage with persistent BBB disruption, microhemorrhages, astrocytic and microglial activation, neuronal loss with significant increase in pTau present both cortical and hippocampal neurons. Moreover, neurogenesis based on BrdU+ neurons were observed in areas of brain atrophy. These results demonstrate the pFUS+MB induced sterile inflammation resulted in damage and pTau production detected by MRI and on histology that could serve as basis for traumatic encephalopathy.

Scientific Focus Area: Neuroscience

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