432.1 - A Phenotypic-based Drug Discovery Approach to Inhibit the Misfolding of Hyperphosphorylated Tau Isoform 1N4R

Jessica Fortin (Purdue University), Kuang-Wei Wang (Michigan State University), Hsiao Chien (Michigan State University), Min-Hao Kuo (Michigan State University)

Mitochondria play a crucial role in Alzheimers disease (AD) onset and progression. Traditional transgenic AD mouse models share the limitation that the proteolytic processing of overexpressed mutant APP results in overproduction of amyloid-beta (Aß) and other APP peptide fragments resulting in artificial, 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, (AppNL-G-F/NL-G-F), termed APP knock-in (APPKI) mice. At 7 months of age, APPKI mice exhibited only learning deficit confirmed by both the water maze test and fear conditioning test. At the same age, we also observed mitochondrial dysfunction consisting of decreased ATP production, higher membrane potential with subsequent greater production of reactive oxygen species (ROS). Furthermore, mitochondria were larger in volume, accompanied by lower molecular markers of mitochondrial dynamics, mitofusin-2 (Mfn2), at 6-8 m. In contrast, the oxygen consumption rate (OCR) from 6 m APPKI hippocampal homogenates was similar to that of WT mice. At 12 months of age, APPKI mice exhibited learning and memory deficit, together with significantly decreased mitochondrial oxygen consumption rate detected by high-resolution respirometry. Histopathology revealed minor amyloidosis accompanied by microgliosis (Iba1) as early as 3 months, which became more apparent at 6 and 12 m. These data indicate a wide range of brain mitochondrial dysfunction and associated cognitive deficits in APPKI mice. Moreover, the identified behavioral and bioenergetic alterations in this physiologically relevant AD transgenic mouse model provide a valuable tool to optimize the temporal component for therapeutic interventions to treat AD.

Work in the authorsamp;rsquo; laboratories is supported by Veterans Affairs Merit Award from the
Department of Veterans Affairs BX003671 (B.P.H.)