Amine oxidase activity of β-amyloid precursor protein modulates systemic and local catecholamine levels

Abstract

The catecholamines dopamine (DA), norepinephrine (NE) and epinephrine (E) are neurotransmitters and hormones that mediate stress responses in tissues and plasma. The expression of β-amyloid precursor protein (APP) is responsive to stress and is high in tissues rich in catecholamines. We recently reported that APP is a ferroxidase, subsuming, in neurons and other cells, the iron-export activity that ceruloplasmin mediates in glia. Here we report that, like ceruloplasmin, APP also oxidizes synthetic amines and catecholamines catalytically (K(m) NE=0.27 mM), through a site encompassing its ferroxidase motif and selectively inhibited by zinc. Accordingly, APP knockout mice have significantly higher levels of DA, NE and E in brain, plasma and select tissues. Consistent with this, these animals have increased resting heart rate and systolic blood pressure as well as suppressed prolactin and lymphocyte levels. These findings support a role for APP in extracellular catecholaminergic clearance.

Rare variants in β-Amyloid precursor protein (APP) and Parkinson’s disease

“…Next to the well-recognized role in amyloid production, recently several other functions have been identified. 23,24 APP has been described to serve as a neuronal ferroxidase, which oxidizes Fe 2+ and loads Fe 3+ on to the iron transport protein transferrin. 24 Moreover, iron accumulates in mice lacking App.…”

“…App − / − mice also show increased cerebral levels of dopamine and catecholamines owing to a lack of amine catabolism via the amine oxidase function of App. 23 Increased APP expression due to APP variants potentially related to PD could lead to cerebral dopamine deficits and a PD phenotype. Accordingly, APP's ferroxidase 24 and amine oxidase 23 activities could even more plausibly fit a potential role in PD pathogenesis or phenotype modification and should be explored further.…”

Parkinson's Disease Iron Deposition Caused by Nitric Oxide-Induced Loss of β-Amyloid Precursor Protein

“…Dissected brain tissue was homogenized in PBS with EDTA-free protease inhibitors (Pierce) and phosphatase inhibitors (Sigma). Iron was measured in homogenate by atomic absorption spectrometry (AAS) as described previously (Ayton et al, 2013). APP (antibody 22C11; in house) was measured by Western blot (4 -12% Bis-Tris gels; Invitrogen), corrected for either ␤-actin (Sigma) or neuron-specific ␤III tubulin (Abcam).…”

“…Striatal dopamine was measured using HPLC with electrochemical detection as described previously (Duce et al, 2013).…”

“…Nigral iron elevation in Parkinson's disease (PD) is reported consistently (Oakley et al, 2007;Salazar et al, 2008;Lei et al, 2012;Ayton et al 2013), affects neurons and glia (Oakley et al, 2007), and is recapitulated in the MPTP model of PD (Lei et al, 2012). Importantly, a selective iron chelator improved PD-motor outcomes in a 12 month randomized clinical trial, achieving a disease-modifying milestone (Devos et al, 2014).…”