Ceruloplasmin, a Potential Therapeutic Agent for Alzheimer's Disease

Ceruloplasmin (CP), a ferrous oxidase enzyme, plays an important role in regulating iron metabolism and redox reactions. Previous studies showed that CP deficiency contributes to Parkinson's disease by increasing iron accumulation and oxidative stress in the substantia nigra. However, the role of CP in Alzheimer's disease (AD) is unclear. We hypothesized that the lack of CP gene expression would affect the pathogenesis and damage of AD by promoting abnormal iron levels and oxidative stress.

AD mouse models were induced in CP knockout mouse either by injection of Aβ_25-35 into the lateral ventricle of the brain or transgenic APP expression. CP levels were decreased significantly in the hippocampus of AD patients, as well as Aβ-CP^+/+ and APP-CP^+/+ mice. Compared to control AD mice, CP gene deletion increased memory impairment and iron accumulation, which could be associated with elevated reactive oxygen species (ROS) levels and lead to cell apoptosis mediated through the Bcl-2/Bax and Erk/p38 signaling pathways in Aβ-CP^-/- and APP-CP^-/- mice. In contrast, the restoration of CP expression to CP^-/- mice through injection of an exogenous expression plasmid into the brain ventricle alleviated Aβ-induced neuronal damage in the hippocampus.

CP alterations in iron contents were mediated through DMT1(-IRE) and changes in ROS levels, which in turn attenuated the progression of AD through the Erk/p38 and Bcl-2/Bax signaling pathways.

Our results show a protective role of CP in AD and suggest that regulating CP expression in the hippocampus may provide a new neuroprotective strategy for AD. Antioxid. Redox Signal. 28, 1323-1337.