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Mitochondria Damage as Early Indicator in an APP NL‐G‐F Mouse Model of Alzheimer's Disease
Author(s) -
Savchenko Paul,
Wang Shanshan,
Ichinomiya Taiga,
Wang Dongsheng,
Paul Ethan,
Wagner Steve,
Patel Hemal,
Head Brian
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03367
Subject(s) - mitochondrion , mitochondrial fission , amyloid precursor protein , biology , mitochondrial fusion , gene knockin , microbiology and biotechnology , amyloid (mycology) , genetically modified mouse , alzheimer's disease , transgene , biochemistry , medicine , mitochondrial dna , disease , gene , botany
Traditional transgenic mouse models of Alzheimer's disease (AD) overexpress mutant amyloid precursor protein (APP) in order to increase pathological amyloid b peptide. However, this results in artificial phenotypes due to the non‐clinically relevant overexpression of APP peptide species. To overcome these limitations, mice with a single humanized APP knock‐in (KI) carrying Swedish (K670N/M671L), Arctic (E693G) and Beyreuther/Iberian (I716F) mutations ( APP NL‐G‐F ) have been developed to better reflect the human disease condition. Several groups have characterized the amyloidogenic, neuroinflammatory, and behavioral phenotypes of this mouse. However, to date no group has investigated and characterized the metabolic and mitochondrial phenotype of this mouse at different stages of development. Methods Mitochondria play a key role in both disease onset and progression, therefore detailed mechanistic characterization of mitochondrial and associated‐metabolic dysfunction in this novel AD model is essential. Here, we evaluated mitochondria function, dynamics (fission/fusion) and morphology in APP NL‐G‐F mice using flowcytometry, Immunoblotting and high‐resolution mitochondrial respirometry. Results Mitochondria dysfunction was detected as early as 3‐4 months (m) of age in the hippocampus of App NL‐G‐F mice, with further pathological progression detected at 6‐8 m. Hippocampal mitochondria from 6‐8 m App NL‐G‐F miceexhibited higher membrane potential, decreased ATP production and increased reactive oxygen species (ROS) production. Morphologically, these mitochondria were larger in volume accompanied by lower dynamics (i.e., altered fission/fusion) at 6‐8 m. Interestingly, plasma isolated from these 6‐8 m App NL‐G‐F mice resulted in a mitochondrial dysfunction in Hela cells and human differentiated neurons derived from induced pluripotent stem cells in vitro . Conclusion Our data revealed early mitochondrial dysfunction and associated metabolic changes in the hippocampus and circulatory plasma of App NL‐G‐F mice.Further research may help to develop early AD detection based on mitochondrial/metabolic dysfunction.