RT Journal Article
SR Electronic
T1 Ultrasound-mediated blood-brain barrier disruption improves anti-pyroglutamate3 Aβ antibody efficacy and enhances phagocyte infiltration into brain in aged Alzheimer’s disease-like mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.15.426806
DO 10.1101/2021.01.15.426806
A1 Qiaoqiao Shi
A1 Tao Sun
A1 Yongzhi Zhang
A1 Chanikarn Power
A1 Camilla Hoesch
A1 Shawna Antonelli
A1 Maren K. Schroeder
A1 Barbara J. Caldarone
A1 Nadine Taudte
A1 Mathias Schenk
A1 Thore Hettmann
A1 Stephan Schilling
A1 Nathan J. McDannold
A1 Cynthia A. Lemere
YR 2021
UL http://biorxiv.org/content/early/2021/01/17/2021.01.15.426806.abstract
AB Pyroglutamate-3 amyloid-β (pGlu3 Aβ) is an N-terminally modified, toxic form of amyloid-β that is present in cerebral amyloid plaques and vascular deposits. Using the Fc-competent murine anti-pGlu3 Aβ monoclonal antibody (mAb), 07/2a, we present here a nonpharmacological approach using focused ultrasound (FUS) with intravenous (i.v.) injection of microbubbles (MB) to facilitate i.v. delivery of the 07/2a mAb across the blood brain barrier (BBB) in order to improve Aβ removal and restore memory in aged APP/PS1 mice, an Alzheimer’s disease (AD)-like model of amyloidogenesis.Compared to sham-treated controls, aged APP/PS1 mice treated with 07/2a immediately prior to FUS-mediated BBB disruption (mAb + FUS-BBBD combination treatment) showed significantly better spatial learning and memory in the Water T Maze. FUS-BBBD treatment alone improved contextual fear learning and memory in aged WT and APP/PS1 mice, respectively. APP/PS1 mice given the combination treatment had reduced Aβ42 and pGlu3 Aβ hippocampal plaque burden compared to PBS-treated APP/PS1 mice.Hippocampal synaptic puncta density and synaptosomal synaptic protein levels were also higher in APP/PS1 mice treated with 07/2a just prior to BBB disruption. Increased Iba-1+ microglia were observed in the hippocampi of AD mice treated with 07/2a with and without FUS-BBBD, and APP/PS1 mice that received hippocampal BBB disruption and 07/2a showed increased Ly6G+ monocytes in hippocampal CA3. FUS-induced BBB disruption did not increase the incidence of microhemorrhage in mice with or without 07/2a mAb treatment.Our findings suggest that FUS is useful tool that may enhance delivery of an anti-pGlu3 Aβ mAb for immunotherapy. FUS-mediated BBB disruption in combination with the 07/2a mAb also appears to facilitate monocyte infiltration in this AD model. Overall, these effects resulted in greater sparing of synapses and improved cognitive function without causing overt damage, suggesting the possibility of FUS as a noninvasive method to increase the therapeutic efficacy in AD patients.Competing Interest StatementWe declare that Stephan Schilling is a former and Thore Hettmann, present, employees of Vivoryon Therapeutics N.V., Germany, and hold stock options of the company. Stephan Schilling is an advisor to Vivoryon Therapeutics N.V. Co-senior author, Cynthia A. Lemere, was an unpaid scientific advisory board member for Vivoryon Therapeutics N.V., receives antibodies, and has previously received unrestricted funding from Vivoryon Therapeutics N.V. for some of her past work on pGlu3 Aβ immunotherapy. She serves as a consultant to Biogen and Acumen Pharmaceticals, both of which are developing anti-amyloid immunotherapies. Brigham and Women's Hospital holds two patents related to this work.