Abstract
Amyloid-β (Aβ) plaque deposition in specific brain regions is a pathological hallmark of Alzheimer's disease. However, the mechanism underlying the regional vulnerability to Aβ deposition in Alzheimer's disease is unknown. Herein, we provide evidence that endogenous neuronal activity regulates the regional concentration of interstitial fluid (ISF) Aβ, which drives local Aβ aggregation. Using in vivo microdialysis, we show that ISF Aβ concentrations in several brain regions of APP transgenic mice before plaque deposition were commensurate with the degree of subsequent plaque deposition and with the concentration of lactate, a marker of neuronal activity. Furthermore, unilateral vibrissal stimulation increased ISF Aβ, and unilateral vibrissal deprivation decreased ISF Aβ and lactate, in contralateral barrel cortex. Long-term unilateral vibrissal deprivation decreased amyloid plaque formation and growth. Our results suggest a mechanism to account for the vulnerability of specific brain regions to Aβ deposition in Alzheimer's disease.
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Acknowledgements
We thank R.H. Mach (Washington University School of Medicine, St. Louis) for generously providing methoxy-X04 and X-34. We thank K.H. Ashe (University of Minnesota) for generously providing Tg2576 mice. We thank Eli Lilly and Co. for generously providing m266 and biotinylated 3D6 anti-Aβ antibodies. This work was supported by US National Institutes of Health grants AG033452 (A.W.B.), AG029524 (J.R.C.), AG568127 (J.R.C.), NS06833 (M.E.R.), NS67905 (J.-M.L.), NS32636 (J.-M.L.), AG13956 (D.M.H.), P30NS057105 (D.M.H.) and the Cure Alzheimer's Fund (D.M.H.).
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A.W.B., M.E.R., J.-M.L. and D.M.H. conceived and designed the study. A.W.B. performed Aβ immunohistochemistry, plaque quantification, steady-state microdialysis, Aβx–40 and Aβx–42 ELISAs, lactate assays, western blots, ISF Aβ t1/2 microdialysis, vibrissal deprivation microdialysis and vibrissal stimulation microdialysis experiments. P.Y. performed long-term vibrissal deprivation, multiphoton microscopy and double immunofluorescence experiments. J.H.R. performed sleep/wake experiments, Aβ1–x ELISAs and lactate assays. F.R.S. collected brain tissue and performed X-34 staining. J.R.C. performed sequential PTX-TTX infusion microdialysis experiments. All of the authors discussed the results. A.W.B. wrote the manuscript with critical evaluation from all authors.
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Bero, A., Yan, P., Roh, J. et al. Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat Neurosci 14, 750–756 (2011). https://doi.org/10.1038/nn.2801
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DOI: https://doi.org/10.1038/nn.2801
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