TY - JOUR
T1 - Cathepsin B Improves ß-Amyloidosis and Learning and Memory in Models of Alzheimer’s Disease
AU - Embury, Christine M.
AU - Dyavarshetty, Bhagyalaxmi
AU - Lu, Yaman
AU - Wiederin, Jayme L.
AU - Ciborowski, Pawel
AU - Gendelman, Howard E.
AU - Kiyota, Tomomi
N1 - Funding Information:
This work was supported in part by NIH Grant DA028555, NS036126, NS034239, MH064570, NS043985, MH062261, AG043540 and DOD Grant 421-20-09A to HEG, the Carol Swarts Emerging Neuroscience Fund, start-up funds from the Department of Pharmacology and Experimental Neuroscience, and the Shoemaker Award for Neurodegenerative Research to TK. The authors thank Drs. K. Hsiao-Ashe for providing the Tg2576 mice, K. Duff for M146 L. PS1 mice, T. Ikezu for pAdTrack-APPsw, and R. Klein for the pGFP vector. The authors also thank the University of Pennsylvania Gene Therapy Program for the p5E18RXC1 and pAd∆F6 vectors, Dr. M. Araínga for assistance with proteomics analysis and James R. Talaska (Confocal Laser Scanning Core facility, University of Nebraska Medical Center) for assistance with confocal microscopy.
Publisher Copyright:
© 2016, The Author(s).
PY - 2017/6/1
Y1 - 2017/6/1
N2 - Amyloid-ß (Aß) precursor protein (APP) metabolism engages neuronal endolysosomal pathways for Aß processing and secretion. In Alzheimer’s disease (AD), dysregulation of APP leads to excess Aß and neuronal dysfunction; suggesting that neuronal APP/Aß trafficking can be targeted for therapeutic gain. Cathepsin B (CatB) is a lysosomal cysteine protease that can lower Aß levels. However, whether CatB-modulation of Aß improves learning and memory function deficits in AD is not known. To this end, progenitor neurons were infected with recombinant adenovirus expressing CatB and recovered cell lysates subjected to proteomic analyses. The results demonstrated Lamp1 deregulation and linkages between CatB and the neuronal phagosome network. Hippocampal injections of adeno-associated virus expressing CatB reduced Aß levels, increased Lamp1 and improved learning and memory. The findings were associated with the emergence of c-fos + cells. The results support the idea that CatB can speed Aß metabolism through lysosomal pathways and as such reduce AD-associated memory deficits.
AB - Amyloid-ß (Aß) precursor protein (APP) metabolism engages neuronal endolysosomal pathways for Aß processing and secretion. In Alzheimer’s disease (AD), dysregulation of APP leads to excess Aß and neuronal dysfunction; suggesting that neuronal APP/Aß trafficking can be targeted for therapeutic gain. Cathepsin B (CatB) is a lysosomal cysteine protease that can lower Aß levels. However, whether CatB-modulation of Aß improves learning and memory function deficits in AD is not known. To this end, progenitor neurons were infected with recombinant adenovirus expressing CatB and recovered cell lysates subjected to proteomic analyses. The results demonstrated Lamp1 deregulation and linkages between CatB and the neuronal phagosome network. Hippocampal injections of adeno-associated virus expressing CatB reduced Aß levels, increased Lamp1 and improved learning and memory. The findings were associated with the emergence of c-fos + cells. The results support the idea that CatB can speed Aß metabolism through lysosomal pathways and as such reduce AD-associated memory deficits.
KW - Adeno-associated virus
KW - Gene therapy
KW - Lysosomal degrading enzyme
KW - Proteomics
KW - Radial arm water maze
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U2 - 10.1007/s11481-016-9721-6
DO - 10.1007/s11481-016-9721-6
M3 - Article
C2 - 27966067
AN - SCOPUS:85004115674
SN - 1557-1890
VL - 12
SP - 340
EP - 352
JO - Journal of Neuroimmune Pharmacology
JF - Journal of Neuroimmune Pharmacology
IS - 2
ER -