Transcranial focused ultrasound, pulsed at 40 Hz, activates microglia acutely and reduces Aβ load chronically, as demonstrated in vivo

Abstract

Objective: Iaccarino et al. (2016) [1] exposed 1 h of light flickering at 40 Hz to awake 5XFAD Alzheimer's Disease (AD) mouse models, generating action potentials at 40 Hz, activating~54% of microglia to colocalize with Ab plaque, acutely, and clearing~50% of Ab plaque after seven days, but only in the visual cortex. Hypothesis: Transcranially delivered, focused ultrasound (tFUS) can replicate the results of Iaccarino et al. (2016) [1] but throughout its area of application. Methods: We exposed sedated 5XFAD mice to tFUS (2.0 MHz carrier frequency, 40 Hz pulse repetition frequency, 400 ms-long pulses, spatial peak pulse average value of 190 W/cm 2 ). Acute studies targeted tFUS into one hemisphere of brain centered on its hippocampus for 1 h. Chronic studies targeted comparable brain in each hemisphere for 1 h/day for five days. Results: Acute application of tFUS activated more microglia that colocalized with Ab plaque relative to sham ultrasound (36.0 ± 4.6% versus 14.2 ± 2.6% [mean ± standard error], z ¼ 2.45, p < 0.014) and relative to the contralateral hemisphere of treated brain (36.0 ± 4.6% versus 14.3 ± 4.0%, z ¼ 2.61, p < 0.009). Chronic application over five days reduced their Ab plaque burden by nearly half relative to paired sham animals (47.4 ± 5.8%, z ¼ -2.79, p < 0.005). Conclusion:Our results compare to those of Iaccarino et al. (2016) [1] but throughout the area of ultrasound-exposed brain. Our results also compare to those achieved by medications that target Ab, but over a substantially shorter period of time. The proximity of our ultrasound protocol to those shown safe for non-human primates and humans may motivate its rapid translation to human studies.

Investigating the Mechanism of Cyclodextrins in the Treatment of Niemann‐Pick Disease Type C Using Crosslinked 2‐Hydroxypropyl‐β‐cyclodextrin

“…[ 64,65 ] Moreover, MRIg‐FUS showed therapeutic efficacy per se on phosphorylated Tau and amyloid plaques. [ 66,67 ] In our exploratory study, brain accumulation and diffusion of the 19.3 kDa HPβCD were appreciably improved after only one application of FUS. Therefore, the combination of MRIg‐FUS with the i.v.…”

Elucidating the mechanism of cyclodextrins in the treatment of Niemann-Pick Disease Type C using crosslinked 2-hydroxypropyl-β-cyclodextrin

“…The limited brain delivery and penetration was addressed employing MRIg-FUS, which has been shown to enhance the deposition of different drugs in various organs [57][58][59] while being well tolerated by animals [60][61][62][63] and humans [64,65]. Moreover, MRIg-FUS showed therapeutic efficacy per se on phosphorylated Tau and amyloid plaques [66,67]. In our exploratory study, brain accumulation and diffusion of the 19.3 kDa HPβCD were substantially improved after only one application of FUS.…”

Mutual Interactions between Brain States and Alzheimer’s Disease Pathology: A Focus on Gamma and Slow Oscillations

“…As summarised above, it is clear that a reduction in gamma power is associated with AD pathology, at least in mouse models. Leveraging this knowledge, various invasive and non-invasive neuromodulation approaches have been adopted to modify AD pathology ( Table 2 ) [ 88 , 89 , 90 , 91 , 157 , 158 , 159 , 160 ]. For example, Tsai and her colleagues have elegantly demonstrated that both invasive and non-invasive gamma stimulations can ameliorate AD pathology [ 86 , 89 , 90 , 91 ]: optogenetic induction of gamma oscillations in the hippocampus can reduce amyloid load by activating microglia [ 89 ].…”