
Fabio Di DomenicoSapienza University of Rome | la sapienza · Department of Biochemical Sciences "Alessandro Rossi Fanelli
Fabio Di Domenico
Ph.D in Biochemistry
About
183
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Introduction
Additional affiliations
December 2010 - November 2015
January 2010 - present
May 2009 - July 2010
Publications
Publications (183)
Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular homeostasis, overseeing the expression of a wide array of genes involved in cytoprotective processes such as antioxidant and proteostasis control, mitochondrial function, inflammation, and the metabolism of lipids and glucose. The accumulation of misfolded proteins...
Background
Biological sex influences Alzheimer’s disease (AD) development, particularly concerning brain insulin resistance (bIR) and early energy metabolism defects. Biliverdin reductase‐A (BVR‐A) plays a crucial role in insulin signaling, and its downregulation leads to bIR. However, the sex‐related differences in AD neuropathology and underlying...
Background
Disturbances of protein O‐GlcNAcylation have pointed out as a possible link between altered brain metabolism and cognitive decline. We previously demonstrated the disruption of O‐GlcNAcylation homeostasis, as an effect of altered OGT and OGA regulatory mechanism, and we confirmed the relevance of O‐GlcNAcylation in the appearance of Alzh...
Background
Brain insulin resistance (bIR) heavily impacts on the core pathological processes of aging and Alzheimer disease (AD) since insulin regulates brain metabolism and cognitive functions. A close link among bIR, oxidative stress (OS) and mitochondrial defects exists, that contributes to brain dysfunctions observed in AD. Intriguingly, severa...
Background
Defective mitochondria and aberrant brain mitochondrial bioenergetics are consistent features in syndromic intellectual disability disorders, such as Rett syndrome (RTT), a rare neurologic disorder that severely affects mainly females carrying mutations in the X-linked MECP2 gene. A pool of CB1 cannabinoid receptors (CB1R), the primary r...
Brain insulin resistance links the failure of energy metabolism with cognitive decline in both type 2 Diabetes Mellitus (T2D) and Alzheimer's disease (AD), although the molecular changes preceding overt brain insulin resistance remain unexplored. Abnormal biliverdin reductase-A (BVR-A) levels were observed in both T2D and AD and were associated wit...
Redox reactions play a critical role for intracellular processes, including pathways involved in metabolism and signaling. Reactive oxygen species (ROS) act either as second messengers or generators of protein modifications, fundamental mechanisms for signal transduction. Disturbance of redox homeostasis is associated with many disorders. Among the...
Down syndrome (DS) is the most common condition with intellectual disability and is caused by trisomy of Homo sapiens chromosome 21 (HSA21). The increased dosage of genes on HSA21 is the cause for the initial neurodevelopmental disorder and for further development of cognitive decline, however the molecular mechanisms promoting brain pathology alon...
Alzheimer disease (AD) is associated with multiple etiologies and pathological mechanisms, among which oxidative stress (OS) appears as a major determinant. Intriguingly, OS arises in various pathways regulating brain functions, and it seems to link different hypotheses and mechanisms of AD neuropathology with high fidelity. The brain is particular...
Background
Brain insulin resistance (bIR) is associated with mitochondrial stress, failure of energy metabolism, synaptic loss and ultimately neurodegeneration both in Alzheimer’s disease (AD) and Type 2‐Diabetes Mellitus (T2DM). Our group previously demonstrated that loss of BVR‐A is an early event triggering bIR in AD. Hence, we tested the hypoth...
Background
Down syndrome (DS) individuals are characterized by a variety of pathological phenotypes that manifest with wide variability in the different tissues. At the level of the central nervous system, the accelerated aging phenotype is associated with the risk to develop Alzheimer‐like dementia. A central aspect of neurodegeneration is the clo...
Down syndrome (DS) is the most frequent genetic cause of intellectual disability and is strongly associated with Alzheimer’s disease (AD). Brain insulin resistance greatly contributes to AD development in the general population and previous studies from our group showed an early accumulation of insulin resistance markers in DS brain, already in chi...
Metformin is the most common anti-diabetic drug and a promising therapy for disorders beyond diabetes, including Rett syndrome (RTT), a rare neurologic disease characterized by severe intellectual disability. A 10-day-long treatment rescued aberrant mitochondrial activity and restrained oxidative stress in a female RTT mouse model. However, this tr...
Protein homeostasis or “proteostasis” represent the process that regulates the balance of the intracellular functional and “healthy” proteins. Proteostasis is fundamental to preserve physiological metabolic processes in the cell and it allow to respond to any given stimulus as the expression of components of the proteostasis network is customized a...
The cells possess several mechanisms to counteract the over-production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), including enzymes such as superoxide dismutase, catalase and glutathione peroxidase. Moreover, an important sensor involved in the anti-oxidant response is KEAP1-NRF2-ARE signaling complex. Under oxidative str...
The complexity of Down Syndrome (DS) neurodegeneration involves multiple molecular mechanisms, similar to what observed in Alzheimer's disease (AD) brain, including the deposition of beta-amyloid (Aβ) into senile plaques and tau hyperphosphorylation in neurofibrillary tangles. Intriguingly, several trisomic genes in addition to being primarily link...
Introduction:
Intellectual disability, accelerated aging, and early-onset Alzheimer-like neurodegeneration are key brain pathological features of Down syndrome (DS). Although growing research aims at the identification of molecular pathways underlying the aging trajectory of DS population, data on infants and adolescents with DS are missing.
Meth...
Alzheimer's disease (AD) is the most common form of dementia in the elderly followed by vascular dementia. In addition to clinically diagnosed dementia, cognitive dysfunction has been reported in diabetic patients. Recent studies are now beginning to recognize type 2 diabetes mellitus (T2DM), characterized by chronic hyperglycemia and insulin resis...
The disturbance of protein O-GlcNAcylation is emerging as a possible link between altered brain metabolism and the progression of neurodegeneration. As observed in brains with Alzheimer’s disease (AD), flaws of the cerebral glucose uptake translate into reduced protein O-GlcNAcylation, which promote the formation of pathological hallmarks. A high-f...
Alzheimer’s disease (AD) is the most prevalent form of dementia in the elderly population and has worldwide impact. The etiology of the disease is complex and results from the confluence of multiple mechanisms ultimately leading to neuronal loss and cognitive decline. Among risk factors, aging is the most relevant and accounts for several pathogeni...
Down syndrome (DS) is the most common genomic disorder characterized by the increased incidence of developing early Alzheimer’s disease (AD). In DS, the triplication of genes on chromosome 21 is intimately associated with the increase of AD pathological hallmarks and with the development of brain redox imbalance and aberrant proteostasis. Increasin...
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this
topic has received increasing attention, and many scientists have entered the field. Our knowledge base
and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular
basis updated guidelines for monit...
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this
topic has received increasing attention, and many scientists have entered the field. Our knowledge base
and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular
basis updated guidelines for monit...
Dysregulation of brain insulin signaling with reduced downstream neuronal survival and plasticity mechanisms are fundamental abnormalities observed in Alzheimer disease (AD). This phenomenon, known as brain insulin resistance, is associated with poor cognitive performance and is driven by the inhibition of IRS1. Since Down syndrome (DS) and AD neur...
Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfuncti...
the PDF can be download freely on pubmed.
https://pubmed.ncbi.nlm.nih.gov/33634751/
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monit...
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monit...
Background
High fat diet (HFD) is the most commonly used experimental model of obesity and insulin resistance, resembling the hallmarks of humans metabolic syndromes. It causes detrimental effects on brain function, but the molecular mechanisms involved are still poorly understood. Recent studies show that HFD may lead to the reduction of glucose u...
Background
Alterations of brain insulin signalling are a common pathophysiological mechanism leading to dementia in AD and Type 2‐Diabetes Mellitus (T2DM). These alterations are often associated with mitochondrial stress, failure of energy metabolism, synaptic loss and ultimately neurodegeneration. Studies from our group identified impairment of BV...
Background
Many neurodegenerative disorders in which aberrant protein conformers aggregate into pathological inclusions, such as tauopathies, also present endoplasmic reticulum stress and chronic activation of the PERK branch of the unfolded protein response (UPR). The adaptive effects of the PERK pathway include reduction of translation by transie...
Background
Down syndrome (DS) is related with an increased incidence of Alzheimer’s disease (AD) neuropathology. Among the putative mechanisms leading neurodegeneration, the reduction of cerebral glucose metabolism may trigger brain damage by impacting the hexosamine biosynthetic pathway (HBP). As reported in AD, defective HBP is responsible for fl...
Down syndrome (DS) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans, which results from the triplication of chromosome 21. To search for biomarkers for the early detection and exploration of the disease mechanisms, here, we investigated the protein expression signature of peripheral blood mo...
Protein O-GlcNAcylation is a nutrient-related post-translational modification that, since its discovery some 30 years ago, has been associated with the development of neurodegenerative diseases. As reported in Alzheimer’s disease (AD), flaws in the cerebral glucose uptake translate into reduced hexosamine biosynthetic pathway flux and subsequently...
Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline, and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunct...
A major challenge in neurobiology is the identification of the mechanisms by which protein misfolding leads to cellular toxicity. Many neurodegenerative disorders, in which aberrant protein conformers aggregate into pathological inclusions, present the chronic activation of the PERK branch of the unfolded protein response. The adaptive effects of t...
Biliverdin reductase-A (BVR-A) impairment is associated with increased accumulation of oxidatively-damaged proteins along with the impairment of autophagy in the brain during neurodegenerative disorders. Reduced autophagy inhibits the clearance of misfolded proteins, which then form neurotoxic aggregates promoting neuronal death. The aim of our stu...
Compelling evidence supports the role of oxidative stress in Alzheimer’s disease (AD) pathophysiology. Interestingly, Herpes simplex virus-1 (HSV-1), a neurotropic virus that establishes a lifelong latent infection in the trigeminal ganglion followed by periodic reactivations, has been reportedly linked both to AD and to oxidative stress conditions...
Metformin is the first-line therapy for diabetes, even in children, and a promising attractive candidate for drug repurposing. Mitochondria are emerging as crucial targets of metformin action both in the periphery and in the brain. The present study evaluated whether treatment with metformin may rescue brain mitochondrial alterations and contrast t...
Dysregulation of insulin signaling pathway with reduced downstream neuronal survival and plasticity mechanisms is a fundamental abnormality observed in Alzheimer's disease (AD) brain. This phenomenon, known as brain insulin resistance, is associated with poor cognitive performance and is driven by the uncoupling of insulin receptor (IR) from its di...
The ultraviolet (UV) component of solar radiation is the major driving force of skin carcinogenesis. Most of studies on UV carcinogenesis actually focus on DNA damage while their proteome-damaging ability and its contribution to skin carcinogenesis have remained largely underexplored. A redox proteomic analysis of oxidized proteins in solar-induced...
Introduction: Autophagy is one of the most conserved clearance systems through which eukaryotes manage to handle dysfunctional and excess organelles and macromolecules. This catabolic process has not only a role in the maintenance of basal turnover of cellular components, but it is also essential in cells adaptation to stress conditions. In the las...
A decline in mitochondrial function plays a key role in the aging process and increases the incidence of age-related disorders, including Alzheimer disease (AD). Mitochondria—the power station of the organism—can affect several different cellular activities, including abnormal cellular energy generation, response to toxic insults, regulation of met...
Impairment of biliverdin reductase-A (BVR-A) is an early event leading to brain insulin
resistance in AD. Intranasal insulin (INI) administration is under evaluation as a
strategy to alleviate brain insulin resistance; however, the molecular mechanisms
underlying INI beneficial effects are still unclear. We show that INI improves insulin
signalling...
Increasing evidences support the notion that the impairment of intracellular degradative machinery is responsible for the accumulation of oxidized/misfolded proteins that ultimately results in the deposition of protein aggregates. These events are key pathological aspects of “protein misfolding diseases” including Alzheimer disease (AD). Interestin...
Hyper-active GSK-3β favors Tau phosphorylation during the progression of Alzheimer's disease (AD). Akt is one of the main kinases inhibiting GSK-3β and its activation occurs in response to neurotoxic stimuli including, i.e., oxidative stress. Biliverdin reductase-A (BVR-A) is a scaffold protein favoring the Akt-mediated inhibition of GSK-3β. Reduce...
Biliverdin reductase-A (BVR-A) is a serine/threonine/tyrosine kinase involved in the regulation of insulin signaling. In vitro studies have demonstrated that BVR-A is a substrate of the insulin receptor and regulates IRS1 by avoiding its aberrant activation, and in animal model of obesity the loss of hepatic BVR-A has been associated with glucose/i...
Background:
Down syndrome (DS) individuals, by the age of 40s, are at increased risk to develop Alzheimer-like dementia, with deposition in brain of senile plaques and neurofibrillary tangles. Our laboratory recently demonstrated the disturbance of PI3K/AKT/mTOR axis in DS brain, prior and after the development of Alzheimer Disease (AD). The aberr...
Alzheimer's disease (AD) is a progressive form of dementia characterized by increased production of amyloid-β plaques and hyperphosphorylated tau protein, mitochondrial dysfunction, elevated oxidative stress, reduced protein clearance, among other. Several studies showed systemic modifications of immune and inflammatory systems due, in part, to dec...
Brain insulin resistance is associated with an increased Aβ production in AD although the molecular mechanisms underlying this link are still largely unknown. Biliverdin reductase-A (BVR-A) is a unique Ser/Thr/Tyr kinase regulating insulin signalling. Studies from our group, demonstrated that BVR-A impairment is among the earliest events favoring b...
Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive loss of memory, reasoning and other cognitive functions. Pathologically, patients with AD are characterized by deposition of senile plaques (SPs), formed by β-amyloid (Aβ), and neurofibrillary tangles (NTFs) that consist of aggregated hyperphosphorylated tau protein...
PET scan analysis demonstrated the early reduction of cerebral glucose metabolism in Alzheimer disease (AD) patients that can make neurons vulnerable to damage via the alteration of the hexosamine biosynthetic pathway (HBP). Defective HBP leads to flawed protein O-GlcNAcylation coupled, by a mutual inverse relationship, with increased protein phosp...
Down Syndrome (DS) individuals by the age of 40s are at increased risk to develop Alzheimer's dementia (AD), with deposition of senile plaques and neurofibrillary tangles. Aberrant mTOR signaling in the brain affects multiple pathways including energy metabolism, mitochondrial function, oxidative stress and autophagy, that are key players in age-re...
Alzheimer's disease (AD) is a progressive form of dementia characterized by increased production of amyloid-β plaques and hyperphosphorylated tau protein, mitochondrial dysfunction, elevated oxidative stress (OS), reduced protein clearance among others. Several studies showed systemic modifications of immune and inflammatory systems due, in part, t...
Down syndrome (DS) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans, which results from the triplication of chromosome 21. DS individuals have an increased risk of developing Alzheimer's disease (AD)-like pathology and dementia by the age of 40 due to the triplication of several genes involv...
Down syndrome (DS), the most frequent chromosomal abnormality in humans, results from complete or partial trisomy of chromosome 21 (Chr21). Though there is intellectual disability in DS people from birth, at about 40-50 years of age conversion to Alzheimer disease (AD)-like neuropathology and dementia often occurs. The mammalian target of rapamycin...
The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase involved in the regulation of protein synthesis and degradation, longevity and cytoskeletal formation. The mTOR pathway represents a key growth and survival pathway involved in several diseases such as cancer, obesity, cardiovascular disease and neurodegenerative diseases...
PET studies have demonstrated the early deficiency of cerebral glucose metabolism in AD patients. Reduced glucose utilization lead to altered protein O-GlcNAcylation, which might represent a link between glucose hypometabolism and the progression of AD. Increasing evidence support, in AD brain, a general decrease of protein O-GlcNAcylation coupled...
Down Syndrome (DS) individuals by the age of 40ys develop a type of dementia that has the same characteristics as Alzheimer disease (AD). Previous studies in DS and AD brain suggest common neurodegenerative pathways including mitochondrial dysfunction, oxidative stress (OS) and reduced glucose metabolism. In addition, several studies suggest a link...