Kunitz Protease Inhibitor‐containing Amyloid Precursor Protein isoforms impaired mitochondrial function

Reduced glucose metabolism is an early feature in Alzheimer's disease (AD), preceding the onset of the clinical symptoms of dementia and the appearance of the neuropathological amyloid‐beta (Aβ) deposits. Studies have shown that this metabolic deficit is associated with altered expression and activity of enzymes involved in mitochondrial energy production. However, the cause of this aberration is unclear. Aβ is proteolytically derived from amyloid precursor protein (APP), and there are three major splice forms of APP in the human brain; APP 695 , APP 751 ,and APP 770 . In the brain, the predominant isoform transcript appears to be APP 695 , coupled with moderately high levels of APP 751 and APP 770 . The APP 751 and APP 770 isoforms contain a Kunitz protease inhibitory (KPI) motif that APP 695 lacks, and APP 770 possesses an additional OX2 domain that is absent in both APP 695 and APP 751 . In AD‐afflicted human brain tissues, APP 751 and APP 770 expression were elevated. In this study, we found that neuronal cell lines expressing KPI‐containing APP isoforms are associated with increased production of Aβ42 and impairment of mitochondrial function. In addition, the KPI‐APP isoforms have a greater propensity to co‐localize with mitochondrial‐specific protein markers. This subcellular localization may contribute to the observed aberrant mitochondrial function.