Brain Iron Dyshomeostasis and Ferroptosis in Alzheimer's Disease Pathophysiology: Two Faces of the Same Coin.

Iron is a fundamental metal involved in many cellular and biological processes in all organisms, humans included. Iron homeostasis is finely regulated both systemically and at the level of the Central Nervous System (CNS) to avoid its imbalance; indeed, iron excess is extremely toxic for cells and triggers detrimental oxidative stress increase. Nevertheless, factors such as genetics, environment, and aging can alter the normal iron metabolism leading to diseases, including neurodegenerative disorders such as Alzheimer's disease (AD). AD is the most widespread neurodegenerative disorder of the CNS. Although the precise pathogenesis of AD is not clarified yet, different studies conducted both in mouse models and in patients reported brain iron accumulation, resulting in cognitive, memory, and motor decline. Moreover, the expression of many proteins involved in iron metabolism appears to be altered in the brain, leading to iron deposition and promoting AD progression. In the context of AD, amyloid beta (Aß) and tau hyperphosphorylation, the two hallmarks of the disease, can promote brain iron deposition and subsequent neuronal death. Indeed, although the mechanism of neuronal loss is not fully understood, several evidence demonstrated the involvement of the iron-dependent form of cell death defined as "ferroptosis". In this review, we deepened about the role of iron and iron deregulation in the CNS with a particular focus on its involvement in the pathogenesis of AD. We also discussed the potential role of ferroptosis as a new pathological mechanism related to dementia. Finally, we reviewed recent strategies for treating AD based on the use of iron chelators, antioxidants and ferroptosis inhibitors, paying close attention to iron disorders and the development of new drugs capable of preventing AD.

Biochemical characterization on muscle tissue of a novel biallelic ACO2 mutation in an infant with progressive encephalopathy.

The ACO2 gene encodes the mitochondrial protein aconitate hydratase, which is responsible for catalyzing the interconversion of citrate into isocitrate in the tricarboxylic acid (TCA) cycle. Mitochondrial aconitase is expressed ubiquitously, and deficiencies in TCA-cycle enzymes have been reported to cause various neurodegenerative diseases due to disruption of cellular energy metabolism and development of oxidative stress. We investigated a severe early infantile-onset neurometabolic syndrome due to a homozygous novel variant in exon 13 of the ACO2 gene. The in vitro pathogenicity of this variant of unknown significance was demonstrated by the loss of both protein expression and its enzymatic activity on muscle tissue sample taken from the patient. The patient presented with progressive encephalopathy soon after birth, characterized by hypotonia, progressive severe muscle atrophy, and respiratory failure. Serial brain magnetic resonance imaging showed progressive abnormalities compatible with a metabolic disorder, possibly mitochondrial. Muscle biopsy disclosed moderate myopathic alterations and features consistent with a mitochondriopathy albeit nonspecific. The course was characterized by progressive worsening of the clinical and neurological picture, and the patient died at 5 months of age. This study provides the first report on the validation in muscle from human subjects regarding in vitro analysis for mitochondrial aconitase activity. To our knowledge, no prior reports have demonstrated a correlation of phenotypic and diagnostic characteristics with in vitro muscle enzymatic activity of mitochondrial aconitase in humans. In conclusion, this case further expands the genetic spectrum of ACO2 variants and defines a complex case of severe neonatal neurometabolic disorder.