Antibodies Targeted to the Brain with Image-Guided Focused Ultrasound Reduces Amyloid-β Plaque Load in the TgCRND8 Mouse Model of Alzheimer's Disease

Abstract

Immunotherapy for Alzheimer's disease (AD) relies on antibodies directed against toxic amyloid-beta peptide (Aβ), which circulate in the bloodstream and remove Aβ from the brain [1], [2]. In mouse models of AD, the administration of anti-Aβ antibodies directly into the brain, in comparison to the bloodstream, was shown to be more efficient at reducing Aβ plaque pathology [3], [4]. Therefore, delivering anti-Aβ antibodies to the brain of AD patients may also improve treatment efficiency. Transcranial focused ultrasound (FUS) is known to transiently-enhance the permeability of the blood-brain barrier (BBB) [5], allowing intravenously administered therapeutics to enter the brain [6]–[8]. Our goal was to establish that anti-Aβ antibodies delivered to the brain using magnetic resonance imaging-guided FUS (MRIgFUS) [9] can reduce plaque pathology. To test this, TgCRND8 mice [10] received intravenous injections of MRI and FUS contrast agents, as well as anti-Aβ antibody, BAM-10. MRIgFUS was then applied transcranially. Within minutes, the MRI contrast agent entered the brain, and BAM-10 was later found bound to Aβ plaques in targeted cortical areas. Four days post-treatment, Aβ pathology was significantly reduced in TgCRND8 mice. In conclusion, this is the first report to demonstrate that MRIgFUS delivery of anti-Aβ antibodies provides the combined advantages of using a low dose of antibody and rapidly reducing plaque pathology.

The Size of Blood–Brain Barrier Opening Induced by Focused Ultrasound is Dictated by the Acoustic Pressure

“…This indicates that IC may be associated with the delivery of the reported antibodies and gene vectors, which was further supported by the observation of microhemorrhages and petechial hemorrhages in those studies that performed histologic analyses after FUS sonication. 5,33,35,36 The findings of our histologic analysis of mouse brains sonicated at 0.84 MPa ( Figure 5C) were consistent with the minor microscopic damaging effects reported in those studies. Behavioral tests performed in nonhuman primates after repeated FUS sonication in combination with MBs showed that the procedure did not cause functional damage even in the presence of minimal histologic damage, such as tiny clusters of extravasated red blood cells and a few dark neurons.…”

“…[17][18][19][20] For the relatively larger-size dextrans (500 and 2,000 kDa), IC was found to be the main mechanism for their successful trans-BBB delivery. Cavitation detection has not been reported in previous studies of FUS-enhanced delivery of larger agents, such as antibodies 4,[32][33][34] and gene vectors, 5,35,36 whose MWs are on the same scale as the 500 and 2,000 kDa dextran, respectively. The MI of the FUS used in those studies varied within the range of 0.63 to 1.56, and the MI corresponding to 0.84 MPa (1.5 MHz) in our study was 0.69, which was in the lower end of the aforementioned range.…”

Two-Photon Fluorescence Microscopy Study of Cerebrovascular Dynamics in Ultrasound-Induced Blood—Brain Barrier Opening

“…The BBB can be transiently and selectively disrupted at the US focus without acute (Hynynen et al, 2001) or chronic neuronal damage or impact on the animal behavior (Howles et al, 2010). Transient changes in the BBB permeability open up new windows for noninvasive, targeted drug delivery in the central nervous system (Kinoshita et al, 2006a, b;Raymond et al, 2008;Jordao et al, 2010).…”

The use of transcranial focused ultrasound in CNS diseases

“…В работах J. Jordao и соавт. [62,63] было продемонстрировано, что воздействие ФУЗ увели-чивает накопление в мишени специфических антител к β-амилоиду и эндогенных антител в бляшках у трансген-ных мышей с болезнью Альцгеймера. После процедуры отмечено уменьшение количества и размера бляшек, а также активация глиальных клеток.…”