Safety and Efficacy of Scanning Ultrasound Treatment of Aged APP23 Mice.

Gerhard Leinenga,Jürgen Götz

doi:10.3389/fnins.2018.00055

Abstract

Deposition of amyloid-β (Aβ) peptide leads to amyloid plaques that together with tau deposits characterize the brains of patients with Alzheimer's disease (AD). In modeling this pathology, transgenic animals such as the APP23 strain, that expresses a mutant form of the amyloid precursor protein found in familial cases of AD, have been instrumental. In previous studies, we have shown that repeated treatments with ultrasound in a scanning mode (termed scanning ultrasound or SUS) were effective in removing Aβ and restoring memory functions, without the need for a therapeutic agent such as an Aβ antibody. Considering that age is the most important risk factor for AD, we extended this study in which the mice were only 12 months old at the time of treatment by assessing a cohort of 2 year-old mice. Interestingly, at this age, APP23 mice are characterized by cerebral amyloid angiopathy (CAA) and the presence of occasional microbleeds. We found that SUS in aged mice that have been exposed to four SUS sessions that were spread out over 8 weeks and analyzed 4 weeks later did not show evidence of increased CAA or microbleeds. Furthermore, amyloid was reduced as assessed by methoxy-XO4 fluorescence. In addition, plaque-associated microglia were more numerous in SUS treated mice. Together this adds to the notion that SUS may be a treatment modality for human neurodegenerative diseases.

Highlights

Life expectancy has increased dramatically in the past decades, owing to general lifestyle improvements and better medication; the ensuing dramatic demographic shift in age distribution is associated with an increased prevalence of diseases such as cerebrovascular disease, cancer and dementia (Leinenga et al, 2017)
We aimed to determine whether the cerebral amyloid angiopathy (CAA) and microbleeds that characterize aged APP23 mice (Calhoun et al, 1999) would be features that are augmented by a SUS treatment, and whether there would be a reduction in amyloid in mice with advanced amyloid pathology
Therapeutic ultrasound is a novel potential treatment modality for human neurodegenerative diseases that may only employ an ultrasound sonication facilitated by biologically inert microbubbles or may be used in combination with a therapeutic agent (Leinenga et al, 2016)

Summary

Introduction

Life expectancy has increased dramatically in the past decades, owing to general lifestyle improvements and better medication; the ensuing dramatic demographic shift in age distribution is associated with an increased prevalence of diseases such as cerebrovascular disease, cancer and dementia (Leinenga et al, 2017). In contrast to cerebrovascular disease and cancer, where non-pharmacological therapies play important roles, the focus in neurological disease research has been on drug discovery, despite the fact that delivery of drugs to the brain presents a particular challenge due to the presence of the blood-brain barrier (BBB). Active exchange between the blood and the brain under normal physiological conditions is indicated by the fact that, for example, steady-state brain levels of peripherally administered antibodies are approximately 0.1% of those in the plasma (Levites et al, 2006) Such evidence does not mean that the BBB is not compromised under certain pathological conditions, but rather that the precise nature of the damage is incompletely understood (Gilad et al, 2012; Krueger et al, 2013; Knowland et al, 2014). Cellular senescence can impair BBB function (Murugesan et al, 2012; Lucke-Wold et al, 2014), several lines of evidence from studies of Alzheimer’s disease (AD) show that disruption of the BBB in neurodegenerative disease should not be assumed, with a study published in 2015 reporting a lack of widespread BBB disruption in several mouse models of Alzheimer’s disease, and a similar occurrence of infarcts (one indication of BBB breakdown) in patients with AD and agematched healthy controls (Bien-Ly et al, 2015)

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