Age-Dependent Behavioral and Metabolic Assessment of AppNL−G−F/NL−G−F Knock-in (KI) Mice
Mitochondria play a crucial role in Alzheimer's disease (AD) onset and progression. Traditional transgenic AD mouse models which were widely used in the past decades share a common limitation: The overexpression of APP and overproduction of amyloid-beta (Aβ) are accompanied by other APP peptide...
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ftcdlib:oai:escholarship.org:ark:/13030/qt6vz509fw 2024-06-23T07:50:55+00:00 Age-Dependent Behavioral and Metabolic Assessment of AppNL−G−F/NL−G−F Knock-in (KI) Mice Wang, Shanshan Ichinomiya, Taiga Savchenko, Paul Devulapalli, Swetha Wang, Dongsheng Beltz, Gianna Saito, Takashi Saido, Takaomi C Wagner, Steve L Patel, Hemal H Head, Brian P 2022-01-01 application/pdf https://escholarship.org/uc/item/6vz509fw unknown eScholarship, University of California qt6vz509fw https://escholarship.org/uc/item/6vz509fw public Biochemistry and Cell Biology Biomedical and Clinical Sciences Biological Sciences Neurosciences Dementia Aging Alzheimer's Disease Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Neurodegenerative Acquired Cognitive Impairment Brain Disorders Aetiology 2.1 Biological and endogenous factors Neurological APP cognition deficit fusion/fission dynamic knock-in mitochondria dysfunction Clinical Sciences Biological psychology article 2022 ftcdlib 2024-05-29T00:43:15Z Mitochondria play a crucial role in Alzheimer's disease (AD) onset and progression. Traditional transgenic AD mouse models which were widely used in the past decades share a common limitation: The overexpression of APP and overproduction of amyloid-beta (Aβ) are accompanied by other APP peptide fragments, which could introduce artificial and non-clinically relevant phenotypes. Here, we performed an in-depth and time-resolved behavioral and metabolic characterization of a clinically relevant AD mouse model engineered to express normal physiological levels of APP harboring humanized Swedish (K670N/M671L), Beyreuther/Iberian (I716F), and Arctic (E693G) mutations (App NL-G-F/NL-G-F ), termed APP knock-in (APPKI) mice. Our result showed that APPKI mice exhibited fear learning deficits at 6-m age and contextual memory deficit at 12-m age. Histopathological analysis revealed mild amyloidosis (6E10) accompanied by microgliosis (Iba1) as early as 3 months, which progressed significantly together with significant astrocytosis at 6 and 12 m. We further analyzed hippocampal mitochondrial dysfunction by multiple assays, while 3-m APPKI mice brain mitochondrial function remains a similar level as WT mice. Significant mitochondrial dysfunction characterized by decreased ATP production and higher membrane potential with subsequent overproduction of reactive oxygen species (ROS) was observed in mitochondria isolated from 7-m APPKI mice hippocampal tissue. Morphologically, these mitochondria were larger in volume with a decreased level of mitochondrial fusion protein mitofusin-2 (MFN2). At 12 months, APPKI mice exhibit a significantly decreased total mitochondrial oxygen consumption rate (OCR) in isolated hippocampal mitochondria detected by high-resolution respirometry. These data indicate early mitochondrial dysfunction in the brain at pre-symptomatic age in the App NL-G-F/NL-G-mice, which may play a key role in the progression of the disease. Moreover, the identified behavioral and bioenergetic alterations in this clinically ... Article in Journal/Newspaper Arctic University of California: eScholarship Arctic |
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University of California: eScholarship |
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topic |
Biochemistry and Cell Biology Biomedical and Clinical Sciences Biological Sciences Neurosciences Dementia Aging Alzheimer's Disease Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Neurodegenerative Acquired Cognitive Impairment Brain Disorders Aetiology 2.1 Biological and endogenous factors Neurological APP cognition deficit fusion/fission dynamic knock-in mitochondria dysfunction Clinical Sciences Biological psychology |
spellingShingle |
Biochemistry and Cell Biology Biomedical and Clinical Sciences Biological Sciences Neurosciences Dementia Aging Alzheimer's Disease Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Neurodegenerative Acquired Cognitive Impairment Brain Disorders Aetiology 2.1 Biological and endogenous factors Neurological APP cognition deficit fusion/fission dynamic knock-in mitochondria dysfunction Clinical Sciences Biological psychology Wang, Shanshan Ichinomiya, Taiga Savchenko, Paul Devulapalli, Swetha Wang, Dongsheng Beltz, Gianna Saito, Takashi Saido, Takaomi C Wagner, Steve L Patel, Hemal H Head, Brian P Age-Dependent Behavioral and Metabolic Assessment of AppNL−G−F/NL−G−F Knock-in (KI) Mice |
topic_facet |
Biochemistry and Cell Biology Biomedical and Clinical Sciences Biological Sciences Neurosciences Dementia Aging Alzheimer's Disease Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Neurodegenerative Acquired Cognitive Impairment Brain Disorders Aetiology 2.1 Biological and endogenous factors Neurological APP cognition deficit fusion/fission dynamic knock-in mitochondria dysfunction Clinical Sciences Biological psychology |
description |
Mitochondria play a crucial role in Alzheimer's disease (AD) onset and progression. Traditional transgenic AD mouse models which were widely used in the past decades share a common limitation: The overexpression of APP and overproduction of amyloid-beta (Aβ) are accompanied by other APP peptide fragments, which could introduce artificial and non-clinically relevant phenotypes. Here, we performed an in-depth and time-resolved behavioral and metabolic characterization of a clinically relevant AD mouse model engineered to express normal physiological levels of APP harboring humanized Swedish (K670N/M671L), Beyreuther/Iberian (I716F), and Arctic (E693G) mutations (App NL-G-F/NL-G-F ), termed APP knock-in (APPKI) mice. Our result showed that APPKI mice exhibited fear learning deficits at 6-m age and contextual memory deficit at 12-m age. Histopathological analysis revealed mild amyloidosis (6E10) accompanied by microgliosis (Iba1) as early as 3 months, which progressed significantly together with significant astrocytosis at 6 and 12 m. We further analyzed hippocampal mitochondrial dysfunction by multiple assays, while 3-m APPKI mice brain mitochondrial function remains a similar level as WT mice. Significant mitochondrial dysfunction characterized by decreased ATP production and higher membrane potential with subsequent overproduction of reactive oxygen species (ROS) was observed in mitochondria isolated from 7-m APPKI mice hippocampal tissue. Morphologically, these mitochondria were larger in volume with a decreased level of mitochondrial fusion protein mitofusin-2 (MFN2). At 12 months, APPKI mice exhibit a significantly decreased total mitochondrial oxygen consumption rate (OCR) in isolated hippocampal mitochondria detected by high-resolution respirometry. These data indicate early mitochondrial dysfunction in the brain at pre-symptomatic age in the App NL-G-F/NL-G-mice, which may play a key role in the progression of the disease. Moreover, the identified behavioral and bioenergetic alterations in this clinically ... |
format |
Article in Journal/Newspaper |
author |
Wang, Shanshan Ichinomiya, Taiga Savchenko, Paul Devulapalli, Swetha Wang, Dongsheng Beltz, Gianna Saito, Takashi Saido, Takaomi C Wagner, Steve L Patel, Hemal H Head, Brian P |
author_facet |
Wang, Shanshan Ichinomiya, Taiga Savchenko, Paul Devulapalli, Swetha Wang, Dongsheng Beltz, Gianna Saito, Takashi Saido, Takaomi C Wagner, Steve L Patel, Hemal H Head, Brian P |
author_sort |
Wang, Shanshan |
title |
Age-Dependent Behavioral and Metabolic Assessment of AppNL−G−F/NL−G−F Knock-in (KI) Mice |
title_short |
Age-Dependent Behavioral and Metabolic Assessment of AppNL−G−F/NL−G−F Knock-in (KI) Mice |
title_full |
Age-Dependent Behavioral and Metabolic Assessment of AppNL−G−F/NL−G−F Knock-in (KI) Mice |
title_fullStr |
Age-Dependent Behavioral and Metabolic Assessment of AppNL−G−F/NL−G−F Knock-in (KI) Mice |
title_full_unstemmed |
Age-Dependent Behavioral and Metabolic Assessment of AppNL−G−F/NL−G−F Knock-in (KI) Mice |
title_sort |
age-dependent behavioral and metabolic assessment of appnl−g−f/nl−g−f knock-in (ki) mice |
publisher |
eScholarship, University of California |
publishDate |
2022 |
url |
https://escholarship.org/uc/item/6vz509fw |
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Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_relation |
qt6vz509fw https://escholarship.org/uc/item/6vz509fw |
op_rights |
public |
_version_ |
1802641860190011392 |