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Stimulation of ADAM10 and decrease in plaques by a sleep‐inducing supplement
Author(s) -
Pahan Kalipada
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.037419
Subject(s) - adam10 , hippocampal formation , hippocampus , amyloid precursor protein , western blot , endocrinology , chemistry , pharmacology , neuroscience , alzheimer's disease , medicine , biology , biochemistry , metalloproteinase , disintegrin , matrix metalloproteinase , disease , gene
Background One of the pathologic hallmarks of Alzheimer’s disease (AD) is the presence of extracellular amyloid plaques containing Aβ peptides, which originate from the amyloidogenic proteolytic processing of amyloid precursor protein (APP), through the sequential action of β‐ and γ‐secretases. On the other hand, APP can also be cleaved by a non‐amyloidogenic pathway by α‐secretase “a disintegrin and metalloproteinase” 10 (ADAM10), precluding the formation of Aβ peptides. Therefore, delineating drugs and pathways for stimulating non‐amyloidogenic metabolism of APP and lowering plaques is an important area of research. We have seen that oleamide, a sleep‐inducing supplement in human, is present in hippocampal nuclei as a ligand of peroxisome proliferator‐activated receptor alpha (PPARα). Method We monitored ADAM10 and ADAM17 in cultured neurons as well as in vivo in the hippocampus of 5xFAD mice by Western blot and immunohistochemistry. Amyloid plaque was monitored in the hippocampus of oleamide‐fed and unfed 5xFAD mice by Western blot and immunostaining. We also recorded cognitive activities by Barnes maze, T maze and novel object recognition test. Result This study underlines the importance of oleamide in increasing the expression of ADAM10 in neurons via PPARα. Moreover, the level of oleamide was less in the hippocampus of 5xFAD mice as compared to non‐Tg mice. Oral administration of oleamide increased the level of this molecule in the hippocampus to stimulate ADAM10, reduce plaques and improve memory and learning in 5xFAD mice. However, oral oleamide remained unable to upregulate ADAM10, lower cerebral plaque load and improve cognitive behaviors in 5xFAD mice lacking PPARα. Conclusion These results indicate an essential role of PPARα in oleamide‐mediated stimulation of non‐amyloidogenic pathway and suggest that this sleep‐inducing supplement may have therapeutic importance for AD. Supported by Zenith Fellows Award (ZEN‐17‐ 438829) and a grant from NIH (AG050431).