TY - JOUR
T1 - Combination anti-Aß treatment maximizes cognitive recovery and rebalances mTOR signaling in APP mice
AU - Chiang, Angie C.A.
AU - Fowler, Stephanie W.
AU - Savjani, Ricky R.
AU - Hilsenbeck, Susan G.
AU - Wallace, Clare E.
AU - Cirrito, John R.
AU - Das, Pritam
AU - Jankowsky, Joanna L.
N1 - Funding Information:
This work was supported by National Institutes of Health grant R01 NS092515 and a gift from the Robert A. and Rene E. Belfer Family Foundation (J.L. Jankowsky). A.C.A. Chiang was supported by National Institutes of Health Biology of Aging training grant T32 AG000183 and a Gates Millennium Scholarship. The Monoclonal Antibody/Recombinant Protein Expression Shared Resource at Baylor College of Medicine was funded by National Institutes of Health Cancer Center Support Grant P30 CA125123. The authors declare no competing financial interests.
Funding Information:
We thank Rebecca Corrigan for animal care, Kurt Christensen and Dean Edwards of the Baylor College of Medicine Monoclonal Antibody/Recombinant Protein Expression Core for monoclonal services, Todd Golde and Thomas Ladd for characterizing the monoclonal preparation, Virginia Lee for the gift of NAB61 antibody, Kira Chen for graphical abstract artwork, and members of the Jankowsky laboratory for helpful discussion. This work was supported by National Institutes of Health grant R01 NS092515 and a gift from the Robert A. and Rene E. Belfer Family Foundation (J.L. Jankowsky). A.C.A. Chiang was supported by National Institutes of Health Biology of Aging training grant T32 AG000183 and a Gates Millennium Scholarship. The Monoclonal Antibody/Recombinant Protein Expression Shared Resource at Baylor College of Medicine was funded by National Institutes of Health Cancer Center Support Grant P30 CA125123. The authors declare no competing financial interests. Author contributions: A.C.A. Chiang and J.L. Jankowsky designed the experiments and wrote the paper; A.C.A. Chiang performed animal treatments, histology, immunostaining, Western blotting, and quantitative analyses; A.C.A. Chiang and S.W. Fowler performed mouse behavioral testing; R.R. Savjani wrote the Matlab code used for image analysis, S.G. Hilsenbeck performed statistical modeling, C.E. Wallace and J.R. Cirrito performed in vivo microdialysis; and P. Das performed ELI SA assays.
Publisher Copyright:
© 2018 Chiang et al.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - Drug development for Alzheimer's disease has endeavored to lower amyloid ß (Aß) by either blocking production or promoting clearance. The benefit of combining these approaches has been examined in mouse models and shown to improve pathological measures of disease over single treatment; however, the impact on cellular and cognitive functions affected by Aß has not been tested. We used a controllable APP transgenic mouse model to test whether combining genetic suppression of Aß production with passive anti-Aß immunization improved functional outcomes over either treatment alone. Compared with behavior before treatment, arresting further Aß production (but not passive immunization) was sufficient to stop further decline in spatial learning, working memory, and associative memory, whereas combination treatment reversed each of these impairments. Cognitive improvement coincided with resolution of neuritic dystrophy, restoration of synaptic density surrounding deposits, and reduction of hyperactive mammalian target of rapamycin signaling. Computational modeling corroborated by in vivo microdialysis pointed to the reduction of soluble/exchangeable Aß as the primary driver of cognitive recovery.
AB - Drug development for Alzheimer's disease has endeavored to lower amyloid ß (Aß) by either blocking production or promoting clearance. The benefit of combining these approaches has been examined in mouse models and shown to improve pathological measures of disease over single treatment; however, the impact on cellular and cognitive functions affected by Aß has not been tested. We used a controllable APP transgenic mouse model to test whether combining genetic suppression of Aß production with passive anti-Aß immunization improved functional outcomes over either treatment alone. Compared with behavior before treatment, arresting further Aß production (but not passive immunization) was sufficient to stop further decline in spatial learning, working memory, and associative memory, whereas combination treatment reversed each of these impairments. Cognitive improvement coincided with resolution of neuritic dystrophy, restoration of synaptic density surrounding deposits, and reduction of hyperactive mammalian target of rapamycin signaling. Computational modeling corroborated by in vivo microdialysis pointed to the reduction of soluble/exchangeable Aß as the primary driver of cognitive recovery.
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U2 - 10.1084/jem.20171484
DO - 10.1084/jem.20171484
M3 - Article
AN - SCOPUS:85046808882
SN - 0022-1007
VL - 215
SP - 1349
EP - 1364
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 5
ER -