Amyloid-β plaque reduction, endogenous antibody delivery and glial activation by brain-targeted, transcranial focused ultrasound

Abstract

Noninvasive, targeted drug delivery to the brain can be achieved using transcranial focused ultrasound (FUS), which transiently increases the permeability of the blood-brain barrier (BBB) for localized delivery of therapeutics from the blood to the brain. Previously, we have demonstrated that FUS can deliver intravenously-administered antibodies to the brain of a mouse model of Alzheimer’s disease (AD) and rapidly reduce plaques composed of amyloid-β peptides (Aβ). Here, we investigated two potential effects of transcranial FUS itself that could contribute to a reduction of plaque pathology, namely the delivery of endogenous antibodies to the brain and the activation of glial cells. We demonstrate that transcranial FUS application leads to a significant reduction in plaque burden four days after a single treatment in the TgCRND8 mouse model of AD and that endogenous antibodies are found bound to Aβ plaques. Immunohistochemical and western blot analyses showed an increase in endogenous immunoglobulins within the FUS-targeted cortex. Subsequently, microglia and astrocytes in FUS-treated cortical regions show signs of activation through increases in protein expression and changes in glial size, without changes in glial cell numbers. Enhanced activation of glia correlated with increased internalization of Aβ in microglia and astrocytes. Together these data demonstrate that FUS improved bioavailability of endogenous antibodies and a temporal activation of glial cells, providing evidence towards antibody- and glia-dependent mechanisms of FUS-mediated plaque reduction.

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

“…To determine whether deletion of these peripheral immune cell populations influences AD pathogenesis, we performed a highly sensitive multiplex ELISA to quantify soluble and insoluble levels of Aβ within the brain. Surprisingly, and despite the use of an aggressive model of amyloidosis, we found that all Aβ species examined (Aβ38, 40,42) were elevated nearly twofold in Rag5xfAD vs. WT-5xfAD half-brains ( Fig. 1 A and B).…”

“…Further support for the potential influence of peripheral IgG in the clearance of Aβ pathology has recently been suggested by a group that used transcranial focused ultrasound to transiently open the BBB. Following ultrasound, this group observed a significant reduction in amyloid pathology, which they suggested might be due to increased infiltration of endogenous IgG into the brain (42,43).…”

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

“…[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.…”

“…1 Unfortunately, the majority of the therapeutic agents are larger than the size limit, and thus cannot cross the BBB. Focused ultrasound (FUS) in combination with microbubbles (MBs) is an emerging technique that has been successfully used in trans-BBB delivery of therapeutic agents of various sizes, such as chemotherapeutic drugs (MW B500 Da), 2 neurotrophins (MWB20 kDa), 3 antibodies (MW B150 kDa), 4 and gene vectors (MW B4 MDa). 5 Although neurosurgical, pharmacologic, or physiologic strategies have been developed to circumvent the BBB for brain drug delivery, 1 transcranial FUS in combination with MBs is the only known technique that can induce localized and reversible BBB opening.…”

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.…”