Alzheimer's disease (AD) is the most common form of senile dementia in the US and worldwide but the causes of its pathogenesis are currently unknown. In this study, we examined two processes that have been implicated in the early stages of AD and other forms of neurodegeneration, iron dysregulation and inflammation, both of which can promote the increased production of amyloid precursor protein (APP). We have measured different pools of brain iron in transgenic iron regulatory protein 2 knockout (IRP2-/-) mice in the early stages of neurodegeneration and in affected brain regions from AD patients at different stages of the disease. IRP2-/- mice demonstrated a region specific deficiency in the metabolically active iron pool, loosely bound iron, at the youngest age examined but not at an older age. A decrease in loosely bound iron was also observed in the hippocampus of mild-moderate and severe AD patients. However, when IRP2 expression with respect to the hallmark lesions of AD, amyloid plaques and neurofibrillary tangles (NFTs), was evaluated by immunohistochemistry, no significant differences were found in the intensity of expression or localization of IRP2 between control and AD brains. Thus, a functional iron deficiency was seen before and at the early stages of neurodegeneration in both IRP2-/- mice and AD patients, but the disturbance in human brains did not appear to stem from altered IRP2 expression.

In the second part of the study, we detected inflammatory changes prior to the manifestations of clinical AD by immunophenotyping leukocytes and examining their cytokine production, as well as APP and Aβ expression, in subjects with mild cognitive impairment (MCI), a preclinical stage of AD. The production of the inflammatory cytokines IL-6, IL-8 and IL-10 were increased in stimulated peripheral blood mononuclear cells (PBMCs) from MCI subjects compared to healthy elderly controls. Moreover, APP lymphocyte expression was elevated and an increased proportion of lymphocytes with a concomitant decrease in the proportion of granulocytes were found in MCI subjects. In summary, functional iron deficiency and a tendency toward an inflammatory phenotype were demonstrated to characterize the early stages of neurodegeneration and AD.