Immunotherapy with Aducanumab Restores Calcium Homeostasis in Tg2576 Mice.
Calcium homeostasis plays a major role in maintaining neuronal function under physiological conditions. Amyloid-β (Aβ) initiates pathological processes that include disruption in intracellular calcium levels, so amelioration of the calcium alteration could serve as an indirect functional indicator of treatment efficacy. Therefore, calcium dynamics were used as a measure of functional outcome. We evaluated the effects of the anti-Aβ antibody aducanumab on calcium homeostasis and plaque clearance in aged Tg2576 mice with in vivo multiphoton imaging. Acute topical application of aducanumab to the brain resulted in clearance of amyloid plaques. Although chronic systemic administration of aducanumab in 22-month-old mice did not clear existing plaques, calcium overload was ameliorated over time. Therefore, this antibody likely restores neuronal network function that possibly underlies cognitive deficits, indicating promise as a clinical treatment. In addition, functional readouts such as calcium overload may be a more useful outcome measure to monitor treatment efficacy in models of Alzheimer's disease compared with amyloid burden alone.



Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is currently without a cure. Aducanumab is an anti-amyloid-β antibody being developed for the treatment of AD. Interim analyses of a phase 1b clinical trial have suggested potential beneficial effects on amyloid pathology and cognitive status in patients treated with aducanumab (Sevigny et al., 2016). Here, we show that a murine analog of aducanumab clears amyloid plaques in an acute setting and restores calcium homeostasis disrupted in a mouse model of AD upon chronic treatment. Therefore, we demonstrate that aducanumab reverses a functional outcome measure reflective of neural network activity.
Department of Neurology, MassGeneral Institute of Neurodegenerative Diseases, Massachusetts General Hospital and Harvard Medical School, Massachusetts 02129, and bbacskai@mgh.harvard.edu kkastanenka@mgh.harvard.edu.
Ksenia V
KV
Kastanenka
Biogen, Cambridge, Massachusetts 02142.
Thierry
T
Bussiere
Department of Neurology, MassGeneral Institute of Neurodegenerative Diseases, Massachusetts General Hospital and Harvard Medical School, Massachusetts 02129, and.
Naomi
N
Shakerdge
Biogen, Cambridge, Massachusetts 02142.
Fang
F
Qian
Biogen, Cambridge, Massachusetts 02142.
Paul H
0000-0002-0802-0052
PH
Weinreb
Biogen, Cambridge, Massachusetts 02142.
Ken
K
Rhodes
Department of Neurology, MassGeneral Institute of Neurodegenerative Diseases, Massachusetts General Hospital and Harvard Medical School, Massachusetts 02129, and bbacskai@mgh.harvard.edu kkastanenka@mgh.harvard.edu.
Brian J
BJ
Bacskai
D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D002118:Calcium / Q000378:metabolism*; D015536:Down-Regulation; D006706:Homeostasis / Q000187:drug effects*; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D036641:Microscopy, Fluorescence, Multiphoton; D009415:Nerve Net / Q000187:drug effects / Q000503:physiopathology; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000473:pathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis
D016229:Amyloid beta-Peptides; D061067:Antibodies, Monoclonal, Humanized; D016194:Receptors, N-Methyl-D-Aspartate; C000600266:aducanumab; D002118:Calcium
Alzheimer's disease; BIIB037; aducanumab; amyloid; calcium