Andreas M Grabrucker

Andreas M Grabrucker
University of Limerick | UL · Department of Biological Sciences

Senior Lecturer (Associate Professor)
Lead of the Bio Materials Research Cluster of the Bernal Institute of University of Limerick

About

142
Publications
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Introduction
Using a combination of biochemical, cellular, molecular and behavioral approaches, we investigate the influence of biometals on synaptopathies, focusing on excitatory postsynapses.
Additional affiliations
December 2016 - present
University of Limerick
Position
  • Lecturer
October 2011 - December 2016
Ulm University
Position
  • Juniorprofessor
August 2009 - September 2011
Stanford University
Education
October 2000 - August 2005

Publications

Publications (142)
Article
Full-text available
Autism is a neurodevelopmental disorders characterized by impairments in communication and social behavior, and by repetitive behaviors. Although genetic factors might be largely responsible for the occurrence of autism they cannot fully account for all cases and it is likely that in addition to a certain combination of autism-related genes, specif...
Chapter
Full-text available
Zinc is an essential trace element for humans and plays a critical role both as a structural component of proteins and as a cofactor in about 300 enzymes. Zinc deficiency was, for example, reported to affect the immune response and the endocrine system and to induce and modify brain disorders. Besides hereditary zinc deficiency, zinc deficiency – a...
Article
Full-text available
Gastrointestinal (GI) problems and microbiota alterations have been frequently reported in autism spectrum disorders (ASD). In addition, abnormal perinatal trace metal levels have been found in ASD. Accordingly, mice exposed to prenatal zinc deficiency display features of ASD-like behavior. Here, we model GI development using 3D intestinal organoid...
Article
Full-text available
Proteins of the ProSAP/Shank family act as major organizing scaffolding elements within the postsynaptic density of excitatory synapses. Deletions, mutations or the downregulation of these molecules has been linked to autism spectrum disorders, the related Phelan McDermid Syndrome or Alzheimer's disease. ProSAP/Shank proteins are targeted to synaps...
Article
The blood–brain barrier (BBB) has a significant contribution to homeostasis and protection of the CNS. However, it also limits the crossing of therapeutics and thereby complicates the treatment of CNS disorders. To overcome this limitation, the use of nanocarriers for drug delivery across the BBB has recently been exploited. Nanocarriers can utiliz...
Article
Full-text available
Glioblastoma Multiforme (GBM) is a devastating disease with a low survival rate and few efficacious treatment options. The fast growth, late diagnostics, and off-target toxicity of currently used drugs represent major barriers that need to be overcome to provide a viable cure. Nanomedicines (NMeds) offer a way to overcome these pitfalls by protecti...
Article
Full-text available
Background Atherosclerosis is the primary cause of cardiovascular diseases (CVDs), contributing to more than 33% of the annual deaths globally. Westernized dietary patterns, a high prevalence (50%) of overweight and obesity, and an increased incidence of glucose intolerance and type-2 diabetes are related to atherosclerosis. However, increased dema...
Article
Full-text available
Epidemiological studies have shown a clear association between early life zinc deficiency and Autism Spectrum Disorders (ASD). In line with this, mouse models have revealed prenatal zinc deficiency as a profound risk factor for neurobiological and behavioral abnormalities in the offspring reminiscent of ASD behavior. From these studies, a complex p...
Chapter
Iron, zinc, copper, manganese, molybdenum, cobalt, and possibly, chromium are essential trace metals for humans. Zinc, in particular, is vital for many physiological processes that regulate endocrine and immune functions and control healthy brain development and activity. However, currently, it is estimated that 20 percent of the human population i...
Article
Full-text available
Editorial on the Research Topic Autism Spectrum Disorders and Metal Dyshomeostasis Autism spectrum disorder (ASD) is a multifaceted neurodevelopmental disorder with a complex etiology that appears to be a mixture of underlying environmental and genetic risk factors. Among the environmental risk factors is perinatal metal dyshomeostasis. It is now e...
Article
Full-text available
Autism Spectrum Disorders (ASD) are caused by a combination of genetic predisposition and nongenetic factors. Among the nongenetic factors, maternal immune system activation and zinc deficiency have been proposed. Intriguingly, as a genetic factor, copy-number variations in S100B, a pro-inflammatory damage-associated molecular pattern (DAMP), have...
Book
Full-text available
This book highlights the current state of the art in many areas of ASD. Chapter 1 provides an overview of the epidemiology of ASD and the current knowledge of the underlying pathogenic mechanisms of ASD. Chapter 2 summarizes the diag- nostic criteria and procedures and highlights present and upcoming therapeutic strategies for ASD. Chapter 3 review...
Article
Full-text available
Metal dyshomeostasis plays a significant role in various neurological diseases such as Alzheimer’s disease, Parkinson’s disease, Autism Spectrum Disorders (ASD), and many more. Like studies investigating the proteome, transcriptome, epigenome, microbiome, etc., for years, metallomics studies have focused on data from their domain, i.e., trace metal...
Article
Full-text available
In the last years, research has shown that zinc ions play an essential role in the physiology of brain function. Zinc acts as a potent neuromodulatory agent and signaling ions, regulating healthy brain development and the function of both neurons and glial cells. Therefore, the concentration of zinc within the brain and its cells is tightly control...
Article
Full-text available
Editorial on the Research Topic Interactions of the Nervous System With Bacteria
Article
The objective of this work was to elucidate whether a sperm selection method that combines rheotaxis and microfluidics can improve the selection of spermatozoa over density gradient and swim-up. For this purpose human sperm selected by rheotaxis were compared against density gradient, swim-up and a control group of non-selected spermatozoa in split...
Article
Full-text available
Impairments in social relationships and awareness are features observed in autism spectrum disorders (ASDs). However, the underlying mechanisms remain poorly understood. Shank2 is a high-confidence ASD candidate gene and localizes primarily to postsynaptic densities (PSDs) of excitatory synapses in the central nervous system (CNS). We show here tha...
Chapter
Besides their core symptomatology, patients with autism spectrum disorders (ASDs) often show various comorbidities. Among them, gastrointestinal (GI) dysfunction is frequently observed. Although considerable progress has been made to identify the underlying causes and pathomechanisms of ASD, it is still unclear if, and how, GI problems contribute t...
Chapter
Recently great advancements have been made in the field of intestinal tissue engineering. However, current in vitro intestinal tissue models have not yet successfully recapitulated all of the complex and dynamic physiological parameters of the intestinal tissue. In this chapter we will discuss the complexity of intestinal tissue structure, with our...
Chapter
Full-text available
Trace metals play an important role in the pathophysiology of amyloid precursor protein, amyloid beta, and tau, the key molecules involved in Alzheimer' s disease. Altering trace metal concentrations in the brain has been explored as a therapeutic strategy for Alzheimer' s disease. It is not only the accumulation of metals that drives amyloid beta...
Article
Full-text available
Fear is a fundamental evolutionary process for survival. However, excess or irrational fear hampers normal activity and leads to phobia. The amygdala is the primary brain region associated with fear learning and conditioning. There, Rho GTPases are molecular switches that act as signaling molecules for further downstream processes that modulate, am...
Article
Full-text available
Research has been consistently showing the role of zinc (Zn) in prostate function. In this article, we review the current literature on the anatomy and main functions of the prostate, highlighting the role of zinc. In particular, we will review the etiology of benign prostate enlargement (BPH), its prevalence in men over 50, the likelihood of BPH b...
Book
Biometals in Autism Spectrum Disorders will be the first to focus on trace metals and autism. Compared to other references examining ASDs or metallomics, a focused presentation of the findings of abnormal metal homeostasis in ASD has not yet come to be. This book provides for readers an overview of current findings on trace metal biology with respe...
Article
Full-text available
The essential trace metals iron, zinc, and copper have a significant physiological role in healthy brain development and function. Especially zinc is important for neurogenesis, synaptogenesis, synaptic transmission and plasticity, and neurite outgrowth. Given the key role of trace metals in many cellular processes, it is important to maintain adeq...
Article
Full-text available
Heterozygous mutations of the gene encoding the postsynaptic protein SHANK3 are associated with syndromic forms of autism spectrum disorders (ASDs). One of the earliest clinical symptoms in SHANK3-associated ASD is neonatal skeletal muscle hypotonia. This symptom can be critical for the early diagnosis of affected children; however, the mechanism m...
Article
Full-text available
Glioblastoma (GBM) is the most frequent and aggressive primary tumor of the brain and averages a life expectancy in diagnosed patients of only 15 months. Hence, more effective therapies against this malignancy are urgently needed. Several diseases, including cancer, are featured by high levels of reactive oxygen species (ROS), which are possible GB...
Article
Delivering therapeutics to disease sites is a challenge facing modern medicine. Nanoparticle delivery systems are of considerable interest to overcome this challenge, but these systems suffer from poor clinical translation. It is believed this is, in part, due to incomplete understanding of nanoparticle physico-chemical properties in vivo. To under...
Chapter
The blood-brain barrier (BBB) protects the central nervous system (CNS) from toxins and homeostatic disruptions. However, this barrier also prevents nearly 100% of therapeutics from entering the CNS. The advent of nanoscale drug carriers, in particular metallic-based nanoparticles, shows significant promise to overcome this barrier. These nanoparti...
Chapter
Protein aggregation is a cornerstone in amyloid-forming neurodegenerative diseases that is largely due to al- tered conditions in the biochemistry of key components of the neuronal environment, including metal ions. Indeed, trace neurometals such as calcium, zinc, and copper are vital players in brain neurobiology, whose homeostasis is altered in m...
Chapter
Pre- and perinatal zinc deficiencies have been consistently linked to autism spectrum disorder (ASD) in epidemiological studies. Zinc plays a key role in neurodevelopment and is involved in the same processes that have been identified to be affected in humans and several ASD animal models that are based on the manipulation of genetic and other nong...
Chapter
Essential trace metals play a critical role in brain development throughout fetal and postnatal life. The consequences of deficiencies for the developing brain of infants and young children can be devastating and enduring. For example, low levels of trace metals can affect behavioral and cognitive development and educability. This chapter provides...
Chapter
To establish causality, targeted modification of trace metal levels has been performed in animal models. This chapter summarizes the findings of animal studies and focuses on the description of the behavioral impairments of mice. A particular focus will be on prenatal zinc-deficient mice as they have been carefully characterized in terms of biochem...
Chapter
For many centuries, it is known that certain metals are toxic to our bodies. For example, lead’s toxicity was recorded as early as 2000 BCE, and toxic effects of mercury were reported in the 16th century but were likely known before. However, the cellular and molecular pathomechanisms of these metals are still not entirely known. Toxic metals may i...
Chapter
Essential trace metals need to be absorbed from dietary sources. The required daily dosages for all biometals have been established in recent years. However, these amounts are based on the average demands on the population level, and several factors may influence the individual demand, such as genetic background, immune status, pregnancy, and diet....
Chapter
The human body contains a plethora of elements classified as metals. Their concentrations vary across several orders, a magnitude starting with the common elements such as calcium and magnesium, trace metals such as zinc and copper, and ultratrace elements such as vanadium or gallium. Together the occurrence and levels of metals determine the metal...
Chapter
Metals have been known to influence the physiology of our body since hundreds of years. Therefore, they have not only been explored as a treatment for various diseases but also used as poisons to end lives. However, despite some apparent effects of acute deficiency or excess of some metals, the association of abnormal metal levels with neuropsychia...
Chapter
Altered gut microbial profiles have been reported in humans with ASD and several rodent models of ASD, including BTBR mice, mice with maternal immune activation, maternal valproic acid exposure, and mice with mutations in Shank3. Maternal zinc deficiency also results in altered microbiota composition and an associated increase in proinflammatory ma...
Chapter
Homeostasis of metal ions such as zinc is critical for healthy brain development and function. In particular, zinc deficiency and the resulting imbalance in the Cu/Zn ratio have been associated with autism spectrum disorder (ASD) as a causative risk factor in human and animal studies. Thus, the possibility of influencing trace metal (zinc) status d...
Chapter
Despite hundreds of different candidate genes and numerous nongenetic factors that have been linked to autism spectrum disorder (ASDs), ASDs are diagnosed by the presence of two characteristic behaviors that are present in individuals with ASDs, namely social impairments and repetitive and stereotypic behaviors. Therefore, all discussed causes for...
Chapter
The detection and quantification of metals are essential for metallomics studies as well as for diagnostic purposes in the clinics. Various methods are available to measure metals in biological samples, each of these having advantages and disadvantages. While in the clinic, the focus lies on the assessment of common metals and trace metals, in rese...
Chapter
To investigate the pathomechanisms involved in ASD, human-induced pluripotent stem cell (iPSC) technology has been used as a tool to understand the cellular physiology of human cells characteristic for different organs (e.g., brain, intestine). To that end, iPSCs were generated directly from individuals with ASD, or an ASD-associated mutation was i...
Chapter
Many ASD rodent models have been generated and characterized in the last decade. Especially, the identification of human ASD-associated genes through large genome-wide association studies allowed the investigation of knockout mice to explore the causative role of mutations and their pathomechanisms. In addition, nongenetic risk factors for ASD have...
Chapter
Several epidemiological studies have linked abnormal trace metal homeostasis to autism spectrum disorder (ASD). The results hint toward an early developmental imbalance. Thus, research that investigates trace metal status during pregnancy is especially valuable. However, studies in this area have been rarely performed. This chapter discusses the mo...
Book
Eco-Neurobiology is a field of Neuroscience that investigates how environmental factors impact our brain through development and aging. This book takes the reader on a journey through the most recent findings about how non-genetic factors influence our brain and may contribute to the development of disorders, but also to the every day function of o...
Article
Full-text available
Zinc is an essential trace metal for bacteria of the intestinal flora. Approximately 20% of dietary zinc-intake is used by intestinal bacteria. The microbiome has recently been described as an important factor for healthy brain function via so-called gut-brain interactions. Similarly, zinc deficiency has been associated with neurological problems s...
Chapter
Full-text available
The extracellular aggregation of insoluble protein deposits of amyloid-β (Aβ) into plaques and the hyperphosphorylation of the intracellular protein tau leading to neurofibrillary tangles are the main pathological hallmarks of Alzheimer' s disease (AD). Both Aβ and tau are metal-binding proteins. Essential trace metals such as zinc, copper, and iro...
Article
Full-text available
The accumulation of amyloid β (Aβ) triggers a cascade of toxic events in Alzheimer’s disease (AD). The KLVFF peptide can interfere with Aβ aggregation. However, the peptide suffers from poor bioavailability and the inability to cross the blood–brain barrier. In this work, we study the possibility of adopting nanomedicine to overcome KLVFF limits in...
Article
New approaches integrating stimuli-responsive linkers into prodrugs are currently emerging. These "smart" prodrugs can enhance the effectivity of conventional prodrugs with promising clinical applicability. Oxidative stress is central to several diseases, including cancer. Therefore, the design of prodrugs that respond to ROS stimulus, allowing a s...
Article
Full-text available
Increasing evidence links proteins of the S100 family to the pathogenesis of Alzheimer's disease (AD). S100 proteins are EF-hand calcium-binding proteins with intra-and extracellular functions related to regulation of proliferation, differentiation, apoptosis, and trace metal homeostasis, and are important modulators of inflammatory responses. For...
Article
Full-text available
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by deficits in social interaction and communication, and repetitive behaviors. In addition, co-morbidities such as gastro-intestinal problems have frequently been reported. Mutations and deletion of proteins of the SH3 and multiple ankyrin repeat domains (SHAN...
Article
Full-text available
Research efforts over the past decades have unraveled both genetic and environmental factors, which contribute to the development of autism spectrum disorders (ASD). It is, to date, largely unknown how different underlying causes result in a common phenotype. However, the individual course of development and the different comorbidities might reflec...
Data
Volumetric analysis cascade. Original data were optionally gradient filtered and an intensity thresholding supported the user-defined selection of the respective brain region. Volumetric marked regions were then analyzed for the respective slices.
Data
Volumes relative to TBV. Each measured brain region (not the cortical thickness) was calculated as the percentage of the total brain volume of the same animal. CTRL, controls; L, left; PZD, prenatal zinc-deficient mice; R, right; Shank3, SH3 and multiple ankyrin repeat domains 3; TBV, total brain volume. The mean values in the diagrams are presente...
Data
Sex differences. Animals were split according to sex. CTRL, controls; f, female; L, left; m, male; PZD, prenatal zinc-deficient mice; R, right; Shank3, SH3 and multiple ankyrin repeat domains 3; TBV, total brain volume. The mean values in the diagrams are presented with standard errors of the mean. Significance levels are as follows according to th...
Data
Raw volume data and statistics for Figures 2, 3.
Article
Full-text available
Treating diseases of the central nervous system (CNS) is complicated by the presence of the blood-brain barrier (BBB), a semipermeable boundary layer protecting the CNS from toxins and homeostatic disruptions. However, this layer also excludes almost 100% of therapeutics, impeding the treatment of CNS diseases. The advent of nanoparticles, in parti...
Article
Full-text available
The loss of one copy of SHANK3 (SH3 and multiple ankyrin repeat domains 3) in humans highly contributes to Phelan McDermid syndrome (PMDS). In addition, SHANK3 was identified as a major autism candidate gene. Interestingly, the protein encoded by the SHANK3 gene is regulated by zinc. While zinc deficiency depletes synaptic pools of Shank3, increase...
Article
Restoration of the Chol homeostasis in the Central Nervous System (CNS) could be beneficial for the treatment of Huntington’s Disease (HD), a progressive, fatal, adult-onset, neurodegenerative disorder. Unfortunately, Chol is unable to cross the blood–brain barrier (BBB), thus a novel strategy for a targeted delivery of Chol into the brain is highl...
Article
Full-text available
Neuronal metal ions such as zinc are essential for brain function. In particular synaptic processes are tightly related to metal and protein homeostasis, for example through extracellular metal-binding proteins. One such protein is neuronal S100B, a calcium and zinc binding damage-associated molecular pattern (DAMP), whose chronic upregulation is a...
Article
Full-text available
A number of studies have reported changes in the hemispheric dominance in autism spectrum disorder (ASD) patients on functional, biochemical, and morphological level. Since asymmetry of the brain is also found in many vertebrates, we analyzed whether prenatal zinc deficient (PZD) mice, a mouse model with ASD like behavior, show alterations regardin...
Data
Marker proteins for brain lateralization in PZD mice. Protein was isolated from striatum of both hemispheres and selected marker proteins were analyzed for expression levels at 8 woa. All values were normalized against GAPDH expression. For the analysis, three male animals per group were used and analyses performed in technical triplicates. Statist...
Article
A local dyshomeostasis of zinc ions in the vicinity of amyloid aggregates has been proposed in Alzheimer's disease (AD) due to the sequestration of zinc in senile plaques. While an increase in zinc levels may promote the aggregation of amyloid beta (Aβ), increased brain zinc might also be beneficial rescuing some pathological alterations caused by...
Article
Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceeding...
Article
Full-text available
Zn is essential for growth and development. The bioavailability of Zn is affected by several factors such as other food components. It is therefore of interest, to understand uptake mechanisms of Zn delivering compounds to identify ways to bypass the inhibitory effects of these factors. Here, we studied the effect of Zn amino acid conjugates (ZnAAs...
Article
Genetic factors might be largely responsible for the development of autism spectrum disorder (ASD) that alone or in combination with specific environmental risk factors trigger the pathology. Multiple mutations identified in ASD patients that impair synaptic function in the central nervous system are well studied in animal models. How these mutatio...
Article
Full-text available
RICH2 knockout (RICH2 KO) mice exhibit neophobia in the novel object test. To gain further insight into their anxiety-related phenotype, we subjected these mice to additional behavioral tests to elucidate whether the behavioral abnormality in these mice is a consequence of reduced exploratory motivation, and whether the neophobia is linked specific...
Chapter
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by their core symptoms - delayed acquisition of speech, deficits in social interactions and stereotypic behaviors. Although ASD are classically not categorized as neurodegenerative disorders, abnormal biometal levels are tightly associated with the etiology of the diseas...