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Cited by 23Alzheimer's disease research and treatmentsMitochondrial Function and PathologyDementia and Cognitive Impairment Research

Age-Dependent Behavioral and Metabolic Assessment of AppNL−G−F/NL−G−F Knock-in (KI) Mice

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Wang, Shanshan, Ichinomiya, Taiga, Savchenko, Paul, Devulapalli, Swetha, Wang, Dongsheng, Beltz, Gianna, Saito, Takashi, Saido, Takaomi C. +3 more·2022·Frontiers in Molecular Neuroscience
DOI 10.3389/fnmol.2022.909989PMC PMC9373872
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Abstract

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 relevant AD mouse model provide a valuable tool to optimize the temporal component for therapeutic interventions to treat AD.

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  • Humanized App knockin (KI) and APP transgenic mouse models mimic certain aspects of AD pathogenesis, including progressive amyloidosis, gliosis, and neuroinflammation, as well as network hyperexcitability and cognitive impairment, albeit to different degrees of severity across models and paradigms.

    “Humanized App knockin (KI) and APP transgenic mouse models mimic certain aspects of AD pathogenesis, including progressive amyloidosis, gliosis, and neuroinflammation, as well as network hyperexcitability and cognitive impairment, albeit to different degrees of severity across models and paradigms.15-27”

    From Machine learning reveals prominent spontaneous behavioral changes and treatment efficacy in humanized and transgenic Alzheimer's disease models (2024) · cites this paper as [23]

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  • Spontaneous behavioral abnormalities were age dependent and therefore tracked the progression of AD-related pathological and cognitive alterations.

    “Second, spontaneous behavioral abnormalities were age dependent and therefore tracked the progression of AD-related pathological and cognitive alterations.16,19,23”

    From Machine learning reveals prominent spontaneous behavioral changes and treatment efficacy in humanized and transgenic Alzheimer's disease models (2024) · cites this paper as [23]

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Authors
Wang, S., Ichinomiya, T., Savchenko, P., Devulapalli, S., Wang, D., Beltz, G., Saito, T., Saido, T. C., Wagner, S. L., Patel, H. H., & Head, B. P.
Affiliations
  • University of California San Diego (US)
  • RIKEN (JP)
Corresponding author
Head, Brian P.
ORCID
Venue
Frontiers in Molecular Neuroscience
Publisher
Frontiers Media SA
Published
2022-07-29
Volume
15
Pages
909989-909989
ISSN
1662-5099 (ISSN-L)
DOI
10.3389/fnmol.2022.909989
PMC
PMC9373872
OpenAlex
W4288715198
Cited by
23
References
4
Citations by year
2026: 8 · 2025: 7 · 2024: 6 · 2023: 2
FWCI
2.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Molecular Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • U.S. Department of Veterans Affairs (IK6 BX005229, #BX005229, BX003671)
  • University of California, San Diego
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, APP knock-in mice, APP mutations, amyloid-beta, mitochondrial dysfunction, hippocampus, contextual memory, amyloidosis, microglial activation, astrocyte activation, reactive oxygen species, mitofusin 2, mitochondrial fusion, mitochondrial oxygen consumption, bioenergetics, presymptomatic disease, mouse model

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