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Alzheimer’s disease (AD) remains as a silent and increasing threat to public health. More than 200 clinical trials for AD have ended with disappointing results and basically empty-handed. The amyloid hypothesis as a primary culprit of AD still centralises most of the efforts in the academic and private sectors, but we need to start to explore alternative avenues for early diagnosis and development of effective therapeutic approaches to treat or slow down the progression of neurodegeneration.
Biomarkers and neuroimaging
Diagnosis of AD usually occurs when the symptoms of mental decline are evident. Unfortunately, AD is a progressive neurodegenerative disorder from which there is no return once neuronal damage starts. The desperate need for effective biomarkers for AD have driven the exploration of genomic, metabolomic and proteomic markers in blood, cerebrospinal fluid (CSF) and tissue samples. Genetic biomarkers strongly implicated in early-onset AD include amyloid-β precursor protein (AβPP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2), whereas apolipoprotein E-ε4 (APOE-ε4), bridging integrator 1 (BIN1), clusterin (CLU), phosphatidylinositol binding clathrin assembly lymphoid-myeloid (PICALM) and complement receptor 1 are connected with late-onset AD. Blood-derived biomarkers potentially correlated with AD include proteins: ceruloplasmin, complement factor H, serum amyloid P-complement precursor (SAP), α1-antitrypsin, α2-macroglobulin, complement 3, Apoliprotein E (ApoE), among others; lipids: phosphatidylcholines, lysophosphatidylcholine and acylcarnitines; miRNA signatures and plasma Aβ42/Aβ40 relative levels. Lamentably most the studies and trials have faced problems in diagnostic accuracy, specificity and even reproducibility. Biomarkers of AD in CSF have been analysed extensively. Aβ40/42 peptides and tau in CSF are obviously the main candidates to diagnose and monitor progression of AD, but other proteins like Visilin-like protein 1 (VILIP1), YKL40, neurogranin, beta-secretase 1 (BACE1) and APOE-ε4 have also been screened and in combination with Aβ40/42 and tau.
CSF ferritin is now proposed by Ayton et al as a potential biomarker of neurodegeneration to predict longitudinal changes in AD.1 Ferritin serves in the storage and transport of iron, keeping Fe3+ ions within a safe cage in a stable non-toxic form. Remarkably, deposition of iron in affected areas of the brain has been another pathological feature of AD that correlates with detriment in cognitive performance. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) has created a database of MRI, positron emission tomography (PET) and year-to-year quantification of Aβ42, tau, ApoE, ferritin and other relevant biomarkers.2 Analysis of CSF biomarkers from ADNI of 296 subjects with diagnosed AD pathology in a 5-year period showed that ferritin predicted reducing CSF Aβ42 levels and brain Aβ deposition. The correlated trend between these CSF biomarkers seems to predict AD diagnosis up to 8–10 years sooner depending on the overall amount of CSF ferritin. Alterations in iron metabolism and its regulatory proteins have been implicated as potential mediators of AD, and ferritin as the main Fe transport–storage protein might uncover important clues linking iron deposition and formation of neurotoxic protein aggregates in AD-affected brain areas.
Evidently, there is a critical need for AD biomarkers and neuroimaging methods with improved diagnostic performance and validation; the correlation between ferritin, Aβ, tau and ApoE4 in CSF just put in evidence the complexity of AD, but open an opportunity to continue in the quest for early diagnostic tools for AD and other related neurodegenerative disorders.
Redox homeostasis in affected neurons
Iron accumulation in the brain triggers many neuronal responses. In particular, excessive production of free radicals through redox reactions,3 irreversible alterations of biomolecules (lipid peroxidation, proteins and nucleic acids) and mitochondrial dysfunction are some of the consequences of redox-active iron in the neurons. Free radicals and reactive oxygen species (ROS) generated may alter the antioxidant system producing oxidative stress, potentially damaging biomolecules and organelles, altering cell signalling and electrophysiology, promoting mitochondrial dysfunction and protein aggregation. Ultimately, the damage makes neurons vulnerable to failure, synaptolysis and death.
Alterations in iron metabolism and neurodegeneration
During the course of AD, marked neuronal failure and death correlate with the progress of brain degeneration. Iron-dependent cell death mechanism has recently been described4 and is speculated to be present during development of neurodegenerative diseases. The importance of alterations in cellular redox homeostasis of iron in cell death and neurodegenerative mechanisms has also been highlighted. The main hallmark of AD is the accumulation of misfolded amyloid-β aggregates forming plaques, but it is still not clear if amyloid plaques are the cause or a symptom of AD. Remarkably, the presence of iron increases the aggregation rate of Aβ, but the final fate of all these excess redox-active ions can be within the amyloid plaques into stable aggregates.5 Interestingly, the size of these iron-rich aggregates matched with the size of ferritin, opening the question if the iron present within plaques comes from ferritin or from other neuronal pools like mitochondria. However, increased iron load has been found within amyloid plaques. Extensive proteomic analysis of plaques from AD found heavy and light chains of ferritin in plaques through quantitative mass spectrometry.
Iron is indispensable for normal cellular function, including bioenergetics, electron transport, enzyme cofactor and oxygen transport. But its versatility and efficiency come with a price; through Fenton reaction produces free radicals and ROS that overwhelm the neuronal antioxidant systems, this is particularly evident during ageing. Alzheimer’s is undoubtedly a complex disease; the recent observation that brain iron deposition–mainly related to CSF ferritin–might have a close correlation with amyloid deposition opens up alternative biomarkers to monitor or diagnose AD, which could be combined with brain imaging techniques and other genomic/proteomic biomarkers. Elevated CSF ferritin will identify patients who might be at greater risk for progression of dementia. These findings further support alterations in brain iron homeostasis with potential consequences of high oxidative stress condition in affected neurons as fundamental to AD.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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