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

Shanshan Wang; Taiga Ichinomiya; Paul Savchenko; Swetha Devulapalli; Dongsheng Wang; Gianna Beltz; Takashi Saito; Takaomi C Saido; Steve L Wagner; Hemal H Patel; Brian P Head

doi:10.3389/fnmol.2022.909989

Age-Dependent Behavioral and Metabolic Assessment of App ^{NL- G- F/ NL- G- F} Knock-in (KI) Mice

Front Mol Neurosci. 2022 Jul 29:15:909989. doi: 10.3389/fnmol.2022.909989. eCollection 2022.

Authors

Shanshan Wang^{1

2}, Taiga Ichinomiya^{1

2

3}, Paul Savchenko^{1

2}, Swetha Devulapalli^{1

2}, Dongsheng Wang^{1

2}, Gianna Beltz^{1

2}, Takashi Saito⁴, Takaomi C Saido⁴, Steve L Wagner⁵, Hemal H Patel^{1

2}, Brian P Head^{1

2}

Affiliations

¹ Veterans Affairs San Diego Healthcare System, San Diego, CA, United States.
² Department of Anesthesia, University of California, San Diego, San Diego, CA, United States.
³ Department of Anesthesiology and Intensive Care Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
⁴ Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan.
⁵ Neurosciences Department, University of California, San Diego, San Diego, CA, United States.

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.

Keywords: APP; cognition deficit; fusion/fission dynamic; knock-in; mitochondria dysfunction.

Grants and funding

IK6 BX005229/BX/BLRD VA/United States