Exploring Whether Iron Sequestration within the CNS of Patients with Alzheimer’s Disease Causes a Functional Iron Deficiency That Advances Neurodegeneration

Abstract

The involvement of iron in the pathogenesis of Alzheimer’s disease (AD) may be multifaceted. Besides potentially inducing oxidative damage, the bioavailability of iron may be limited within the central nervous system, creating a functionally iron-deficient state. By comparing staining results from baseline and modified iron histochemical protocols, iron was found to be more tightly bound within cortical sections from patients with high levels of AD pathology compared to subjects with a diagnosis of something other than AD. To begin examining whether the bound iron could cause a functional iron deficiency, a protein-coding gene expression dataset of initial, middle, and advanced stages of AD from olfactory bulb tissue was analyzed for iron-related processes with an emphasis on anemia-related changes in initial AD to capture early pathogenic events. Indeed, anemia-related processes had statistically significant alterations, and the significance of these changes exceeded those for AD-related processes. Other changes in patients with initial AD included the expressions of transcripts with iron-responsive elements and for genes encoding proteins for iron transport and mitochondrial-related processes. In the latter category, there was a decreased expression for the gene encoding pitrilysin metallopeptidase 1 (PITRM1). Other studies have shown that PITRM1 has an altered activity in patients with AD and is associated with pathological changes in this disease. Analysis of a gene expression dataset from PITRM1-deficient or sufficient organoids also revealed statistically significant changes in anemia-like processes. These findings, together with supporting evidence from the literature, raise the possibility that a pathogenic mechanism of AD could be a functional deficiency of iron contributing to neurodegeneration.

Amyloid‐β exposed astrocytes induce iron transport from endothelial cells at the blood–brain barrier by altering the ratio of apo‐ and holo‐transferrin

“…In line with a reduced iron release, we have shown that ECs incubated with holo-Tf have reduced Fpn levels (Baringer, Palsa, et al, 2023;Simpson et al, 2015). Recently, LeVine et al found that iron deficiency, iron transport, and mitochondrial related processes were all upregulated in AD patient tissue (LeVine et al, 2023). Here, we found that Aβ CM contained significantly less iron than control CM.…”

“…Recently, Ayton et al have shown that brain iron accumulation occurs early in AD and prior to widespread Aβ or tau pathology distribution associated with later disease stages (Ayton, Portbury, et al, 2021), suggesting iron uptake dysfunction occurs independently from the vascular damage Aβ can inflict in later stages of the disease (Erickson & Banks, 2013). Anemic and iron transport processes are also upregulated in AD patient brain tissue (LeVine et al, 2023), proposing the hypothesis that the AD brain may operate in functional iron deficiency.…”

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

“…Furthermore, the conditioned media had an increased percentage of apo-transferrin, which stimulated endothelial cells to increase iron transport [25]. In support of this, the expression of transcripts for transferrin was upregulated in the olfactory bulb of patients with early Alzheimer's disease compared to control subjects [5]. Amyloid β was also found to increase the expression of divalent metal transporter 1 (DMT1), which is thought to mediate an increased uptake of non-transferrin-bound iron in immortalized microglia [26] (Figure 1B).…”

“…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]. Once iron becomes unavailable, cells experience a functional iron deficient state that has similarities with anemia [5]. Cells can respond to a functional deficiency of iron by taking up more iron and exporting less iron [4,6].…”

“…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.…”