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

• Main Authors: 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
• Format: Article in Journal/Newspaper
• Language: unknown
• Published: eScholarship, University of California 2022
• Subjects: 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; Arctic
• Online Access: https://escholarship.org/uc/item/6vz509fw

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 ...