Examining the Role of a Functional Deficiency of Iron in Lysosomal Storage Disorders with Translational Relevance to Alzheimer’s Disease

Abstract

The recently presented Azalea Hypothesis for Alzheimer’s disease asserts that iron becomes sequestered, leading to a functional iron deficiency that contributes to neurodegeneration. Iron sequestration can occur by iron being bound to protein aggregates, such as amyloid β and tau, iron-rich structures not undergoing recycling (e.g., due to disrupted ferritinophagy and impaired mitophagy), and diminished delivery of iron from the lysosome to the cytosol. Reduced iron availability for biochemical reactions causes cells to respond to acquire additional iron, resulting in an elevation in the total iron level within affected brain regions. As the amount of unavailable iron increases, the level of available iron decreases until eventually it is unable to meet cellular demands, which leads to a functional iron deficiency. Normally, the lysosome plays an integral role in cellular iron homeostasis by facilitating both the delivery of iron to the cytosol (e.g., after endocytosis of the iron–transferrin–transferrin receptor complex) and the cellular recycling of iron. During a lysosomal storage disorder, an enzyme deficiency causes undigested substrates to accumulate, causing a sequelae of pathogenic events that may include cellular iron dyshomeostasis. Thus, a functional deficiency of iron may be a pathogenic mechanism occurring within several lysosomal storage diseases and Alzheimer’s disease.

Immunological Profile and Markers of Endothelial Dysfunction in Elderly Patients with Cognitive Impairments

“…We also found a radical decrease in iron levels in the SIVD patients, which was one of the most characteristic features of this group. The recently presented Azalea Hypothesis for Alzheimer's disease asserts that iron becomes sequestered, leading to a functional iron deficiency that contributes to neurodegeneration [58]. Iron sequestration can occur by iron being bound to protein aggregates, such as amyloid-β and tau, iron-rich structures not undergoing recycling (e.g., due to disrupted ferritinophagy and impaired mitophagy), and the diminished delivery of iron from the lysosome to the cytosol.…”

“…Reduced iron availability for biochemical reactions causes cells to respond by acquiring additional iron, resulting in an elevation in the total iron level within the affected brain regions. As the amount of unavailable iron increases, the level of available iron decreases until, eventually, it is unable to meet cellular demands, leading to a functional iron deficiency [58].…”

Exploring Potential Mechanisms Accounting for Iron Accumulation in the Central Nervous System of Patients with Alzheimer’s Disease

“…A functional iron deficiency can lead cells to perceive a low iron status, thereby causing compensatory mechanisms [6]. Iron can become sequestered and unavailable for use by multiple mechanisms resulting in a functional iron deficiency.…”

“…Besides becoming trapped in protein aggregates (e.g., amyloid β, tau, α synuclein), iron can become unavailable by processing defects (e.g., impaired delivery of iron from the lysosome to the cytosol or mitochondria), diminished recycling (e.g., disrupted mitophagy), decreased production or altered metabolism of heme and iron-containing proteins, etc. [4,[6][7][8] (Figure 1). In addition, as a CNS disease advances, iron from degenerating cells can become sequestered within reactive microglia [9][10][11], which accumulate ferritin [12][13][14].…”

“…Common themes for CNS iron accumulation may be the need to acquire extra iron to make up for a functional iron deficiency in order to maintain support for essential biochemical reactions, or to address an increased requirement for iron, e.g., due to an upregulation or alteration of metabolic processes. The former mechanism, a functional iron deficiency, has been postulated to occur in Alzheimer's disease as well as some other neurological conditions [4][5][6], while the latter mechanism may occur as a corollary to inflammation, development, insulin resistance, or diabetes. Thus, the reasons leading to elevated levels of CNS iron may vary.…”