Overdosing on iron: Elevated iron and degenerative brain disorders

Abstract

All cells in organisms ranging from yeast to humans utilize iron as a cofactor or structural element of proteins that function in diverse and critical cellular functions. However, deregulation of the homeostatic mechanisms regulating iron metabolism resulting in a reduction or excess of iron within the cell or outside of it can have serious effects to the health of cells and the organism. This review provides a brief overview of the molecular and cellular mechanisms regulating iron physiology, including the molecules and processes regulating iron uptake, its storage and utilization, its recycling, and its release from the cell, such that the cellular iron levels are sufficient to meet metabolic demand but below those that cause permanent damage. The major focus of review is on the pathological consequences of dysregulation of these homeostatic mechanisms, focusing on the brain. Current advances on the role of iron accumulation to the pathogenesis of rare neurological disorders caused by genetic mutations as well as to the more prevalent and age-associated neurodegenerative diseases are described. Impact statement Brain degenerative disorders, which include some neurodevelopmental disorders and age-associated diseases, cause debilitating neurological deficits and are generally fatal. A large body of emerging evidence indicates that iron accumulation in neurons within specific regions of the brain plays an important role in the pathogenesis of many of these disorders. Iron homeostasis is a highly complex and incompletely understood process involving a large number of regulatory molecules. Our review provides a description of what is known about how iron is obtained by the body and brain and how defects in the homeostatic processes could contribute to the development of brain diseases, focusing on Alzheimer’s disease and Parkinson’s disease as well as four other disorders belonging to a class of inherited conditions referred to as neurodegeneration based on iron accumulation (NBIA) disorders. A description of potential therapeutic approaches being tested for each of these different disorders is provided.

Porphyromonas Gingivalis May Seek the Alzheimer’s Disease Brain to Acquire Iron from Its Surplus

“…Ferritin accumulated mainly at the edge of A␤ plaques, while a smaller amount of free iron was observed in the plaque-free tissue, as well as in and around A␤ plaques [24]. Secreted ferritin, which reflects the intracellular iron load, was increased in the cerebrospinal fluid of individuals with mild cognitive impairment and may be used to predict a near-term progression risk of the disease [2]. Accordingly, free iron and ferritin accumulation seem to follow the formation of amyloid plaques.…”

“…The latter are microtubule-associated proteins composed of filaments of hyperphosphory-lated tau. Both types of hallmark proteins are probably acting synergistically in the pathogenesis of AD (for a review, see [2]).…”

“…Iron can be found in the human brain where its levels increase with age [1,2]. Importantly, iron accelerates the aggregation of the amyloid-␤ (A␤) peptide [3][4][5][6] and is abundant in A␤ plaques [7].…”

“…This chemistry is used by cells for many redox reactions but can cause deleterious oxidative stress which contributes to AD [8]. Specifically, Fe 3+ accumulates in A␤ plaques and neurofibrillary tangles (NFTs) of AD brains and is the more potent of the two ions in neurotoxicity [2]. Everett et al [13] found A␤ capable of accumulating Fe 3+ within their aggregates, which resulted in A␤-mediated reduction of Fe 3+ to a redox-active iron ( 2+ ) phase.…”

“…These authors detected a specific tau strain in AD by using immunohistochemistry with novel conformation-selective tau antibodies that distinguished it from non-AD tauopathies. A␤ and tau can also disrupt iron homeostasis [2]. This suggests a positive-feedback pathogenic process in AD.…”