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.
SIGNIFICANCE STATEMENT: 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.