Dysregulation of Neuronal Iron Homeostasis as an Alternative Unifying Effect of Mutations Causing Familial Alzheimer’s Disease

Abstract

The overwhelming majority of dominant mutations causing early onset familial Alzheimer’s disease (EOfAD) occur in only three genes, PSEN1, PSEN2, and APP. An effect-in-common of these mutations is alteration of production of the APP-derived peptide, amyloid β (Aβ). It is this key fact that underlies the authority of the Amyloid Hypothesis that has informed Alzheimer’s disease research for over two decades. Any challenge to this authority must offer an alternative explanation for the relationship between the PSEN genes and APP. In this paper, we explore one possible alternative relationship – the dysregulation of cellular iron homeostasis as a common effect of EOfAD mutations in these genes. This idea is attractive since it provides clear connections between EOfAD mutations and major characteristics of Alzheimer’s disease such as dysfunctional mitochondria, vascular risk factors/hypoxia, energy metabolism, and inflammation. We combine our ideas with observations by others to describe a “Stress Threshold Change of State” model of Alzheimer’s disease that may begin to explain the existence of both EOfAD and late onset sporadic (LOsAD) forms of the disease. Directing research to investigate the role of dysregulation of iron homeostasis in EOfAD may be a profitable way forward in our struggle to understand this form of dementia.

Accelerated loss of hypoxia response in zebrafish with familial Alzheimer’s disease-like mutation of Presenilin 1

“…These observations of human brain aging, our data on acceleration of aging in fAD-like mutants, and the hypoxia response data we have presented here, are consistent with a view of AD as both a normal possible outcome of aging and as a pathological, hypometabolic brain state. The data we have presented here are consistent with the "stress threshold change-of-state" model of AD progression we have previously presented [12]. This model postulates aged brains "inverting" (in terms of numerous molecular characteristics) into a pathological state as the brains reach homeostatic stress limits such as their limit to cope with the increasing oxidative stress resulting from increasing hypoxia.…”

“…This raises the possibility that the increased expression of HIF-1-target genes in young psen1 mutant brains may actually be due to decreased cytosolic Fe 2+ availability (that stabilises HIF-1) rather than hypoxia. Hypothetically, this situation might arise because correct acidification of the endo-lysosomal pathway is required for most iron importation and for recycling of the iron in damaged mitochondria and in ferritin into its Fe 2+ form via autophagy (reviewed in [12]). fAD mutations in the PRESENILINs apparently decrease lysosomal acidification [60] and this is predicted to decrease Fe 2+ availability.…”

“…Meanwhile, the fAD gene APP that encodes the protein precursor of the A peptide, plays a role in iron export since full-length APP, (and at least one secreted form of APP, sAPP), can stabilise Ferroportin to increase export of Fe 2+ from neurons [61,62]. These phenomena have led us to propose that fAD mutations in the PSEN genes and APP may share common roles in iron dyshomeostasis [12]. The increased expression of HIF-1-target genes we have observed in the brains of young adult zebrafish is consistent with this idea.…”

“…PSEN mutations are viewed mostly as altering cleavage of APP to yield changes in the relative abundance of different Aβ size forms. However, on a population basis, the majority of fAD mutations occur in the gene PSEN1 [10] and the relationship between fAD mutations in the PRESENILIN genes and APP is still a matter of debate [11,12].…”

Amyloid‐β immunotherapy for alzheimer disease: Is it now a long shot?

“…Although longitudinal studies show that such subjects may be at risk for future cognitive impairment, that impairment may be minor and clinically irrelevant . Even if brain amyloid deposition in these subjects does parallel cognitive decline over time, it may still be secondary to other processes . Because Aβ deposition starts with progressive aggregation of soluble oligomers, it seems likely that these individuals have been exposed to Aβ oligomers (and any neurotoxic effects) for a long time.…”