People with autism spectrum disorder (ASD) appear to suffer malfunctions in a cell that produces a special coating around nerve fibers that facilitates efficient electrical communication across the brain.
And correcting it could offer a potential new avenue for treatment, according to a new study published today in the journal Nature Neuroscience from scientists at the Lieber Institute for Brain Development (LIBD).
“This could be a sea change in our understanding of what causes people to suffer this serious brain disorder,” said Daniel R. Weinberger, M.D., LIBD CEO & Director. “We’re actively testing in experimental models drugs that might correct this abnormality.”
The study revealed that people who suffer from ASD have a cellular abnormality that impairs production of myelin, a fatty substance that creates an insulative sheath around nerve fibers in the brain that allows them to efficiently communicate with one another.
The production of myelin is part of a biological process critical to early brain development known as myelination, which Weinberger compared to laying a network of fiber optic cable across the brain that facilitates a range of neurological processes.
Brady Maher, Ph.D., LIBD’s lead investigator on the study, said that in trying to understand the root causes of ASD, most researchers have focused on potential problems with neurons, the principal cells of the brain.
But he said our new study indicates that problems with a supporting cell that is critical for insulating the nerve fibers may be a previously underappreciated mechanism.
“Myelination is essential to healthy brain development, it’s a process that begins just before birth and continues throughout the lifespan.
If impaired, it leads to abnormal brain development that likely results in communication and behavior challenges associated with ASD,” Maher said.
As the name suggests, ASD can produce a wide spectrum of symptoms, ranging from difficultly navigating social and emotional interactions to severe language and behavior impairments. And while it is sometimes linked to extraordinary talents in certain individuals, even milder forms of ASD can make daily life very challenging.
The new insights into ASD emerged from the Lieber Institute’s research on Pitt-Hopkins syndrome, a rare neurodevelopmental disorder known to produce ASD symptoms, that is caused by mutations in a gene called TCF4.
Working with mice with the same TCF4 gene mutation as people with Pitt-Hopkins, the researchers identified a genetic abnormality that disrupts the function of cells that control myelin production. These cells are called oligodendrocytes or OL for short.
The researchers then explored other ASD mouse models caused by different mutations associated with autism and found consistent evidence for abnormalities in oligodendrocytes.
Remarkably, in a collection of donated brain tissue from deceased people with ASD who did not suffer from Pitt-Hopkins syndrome but had more common forms of ASD, they observed the same abnormality: problems with OL cells that impair myelin production, something that is not found in brains of non-ASD patients.
The study revealed that people who suffer from ASD have a cellular abnormality that impairs production of myelin, a fatty substance that creates an insulative sheath around nerve fibers in the brain that allows them to efficiently communicate with one another. Image is credited to the researchers.
“It appears that in many people who suffer from ASD, their OL cells are not maturing sufficiently or functioning properly,” Maher said.
“This suggests they are not producing enough myelin insulation for their neurons, which could profoundly disrupt brain development and electrical communication in the brain.
He noted that previous studies have shown that people with ASD can exhibit a decrease in myelin thickness in certain regions of the brain.
He said recent evidence, in addition to his own suggests, that people with ASD have fewer OL cells.
But Maher said that previous research had not connected the dots–that there appears to be an underlying biological process in people with ASD limiting the capacity of OL cells to produce the myelin brains need for proper development.
And that deficiency could be a key source of the neurological problems seen in people with this disorder.
Also, he said given the different factors that influence myelin production in OL cells, the defects in myelination could vary considerably across individual cases of ASD, corresponding to the variation in the severity of symptoms across the autism spectrum.
Maher said he and his colleagues at the Lieber Institute are now testing compounds that may have the capacity to boost myelination in the brain.
“Because myelination is a lifelong process it provides a unique therapeutic opportunity that we can tap into throughout the lifespan.
Along these lines, we are eager to see whether enhancing myelination in these mice can improve their ASD-associated behaviors,” he said. “Promising candidates could then be considered for clinical studies.”
Brain disorders represent a serious threat to human health because of both their high prevalence, which continues to rise in line with increasing life expectancy, as well as their associated disabilities, heavy economic burden, and lack of effective and tolerable treatments .
According to a World Economic Forum report , the global percentage of individuals aged more than 60 years will double from 11% in 2010 to 23% in 2050.
Consistent with aging of the population, cardiovascular diseases, neurodegenerative conditions, and mental health conditions have now become the dominant contributors to the global burden of non-communicable diseases (NCDs).
In fact, mental health conditions are now the leading cause of Disability Adjusted Life Years (DALYs), accounting for 37% of healthy life years lost from NCDs, and their global cost is expected to surge from $2.5 trillion USD in 2010 to $6.0 trillion USD by 2030 .
Neurodegenerative and neuropsychiatric conditions are usually treated symptomatically and currently available drugs generally lack disease-modifying activity, have low efficacy, and/or significant tolerability burdens [2,3,4,5,6].
Hence, there is an urgent need to identify more effective, low-cost, and easily scalable interventions to prevent and treat neurological, neurodegenerative, and psychiatric disorders.
A growing body of evidence indicates that exercise is effective in the prevention and treatment of various chronic disorders (reviewed in Reference ), including neurodegenerative and neuropsychiatric conditions.
A dipeptide, carnosine (β-alanine-L-histidine), was identified as an exercise enhancer and has been widely used in sports with the aim of improving physical performance and muscle gain .
Carnosine has been shown to favourably affect energy and calcium metabolism, and reduce lactate accumulation [9,10]. Notwithstanding the biochemical complexity of exercise, both exercise and carnosine may exert similar effects including optimization of energy metabolism, improvement of mitochondrial function, and reduction of systemic inflammation, and oxidative stress [11,12,13].
Although 99% of carnosine in the human body is located in skeletal muscle, carnosine is also present in heart muscle as well as in specific areas of the brain at approximately 100-fold lower concentrations [10,12].
Thus, carnosine is found primarily in the two tissues with the most active oxidative metabolism, which are tissues in muscles and the brain.
Both of carnosine’s precursors, β-alanine and L-histidine, can be easily taken up from circulation into the brain through amino acids transporters in the blood-brain barrier (BBB) .
This enables local carnosine synthesis in the brain, which takes place in olfactory neurons  and in glial cells, specifically in mature oligodendrocytes [16,17].
Carnosine itself can also cross the BBB , but it is thought that the majority of brain carnosine is a product of its de novo synthesis localized to specific areas of the brain rather than a result of its penetration through the BBB .
Carnosine together with homocarnosine, which is a dipeptide of gamma-aminobutyric acid (GABA) and histidine and the dominant carnosine analogue in the human brain, are both present in cerebrospinal fluid (CSF) .
The presence of carnosine and its analogues in the brain suggests that these histidine-related compounds may play some physiological role in brain function, as endogenous antioxidants, neuromodulators, and neuroprotective molecules .
However, despite a number of studies demonstrating the anti-ischemic and neuroprotective properties of carnosine, there is currently no unified hypothesis as to the exact role of carnosine in brain disorders, or its potential use in preventing or managing these conditions.
Although previous reviews including systematic reviews and meta-analyses on this topic have been conducted, these tend to focus on specific disorders such as neurodegenerative disorders  or depression , or are limited to human studies, overlooking the large body of evidence derived from experimental and animal models.
Given these limitations and the considerable number of newly published studies, a comprehensive updated review of the evidence in relation to carnosine and brain-related disorders is pertinent.
In this narrative literature review, we aimed to summarize current evidence regarding the potential role of carnosine in brain-related disorders, including neurological, neurodevelopmental, neurodegenerative, and psychiatric disorders from cell, animal, and human studies including clinical trials and meta-analyses.
We did not intend to introduce new data or conclusions but rather to integrate and contextualise the current state of knowledge in this area and to identify relevant evidence gaps.
For the purpose of this review, we define neurological disorders as those conditions with recognisable pathological damage to the brain (e.g., ischemia/stroke), neurodevelopmental disorders as abnormal brain development (e.g., Autistic spectrum disorders), neurodegenerative disorders as involving cell death and degeneration over time (e.g., Alzheimer’s, Parkinson’s), and psychiatric disorders as those which affect mental functioning and behaviour (e.g., schizophrenia, mood disorders).
We searched relevant publications in PubMed using the following keywords without date limits including both clinical and preclinical data: carnosine, β-alanine, L-histidine, anserine, dementia, cognition, Alzheimer disease, mild cognitive impairment, Parkinson disease, multiple sclerosis, stroke, brain ischemia, brain hemorrhage, brain trauma, epilepsy, Autistic spectrum disorders, mood disorders, anxiety, depression, schizophrenia, Attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, post-traumatic disorder, and dyslexia.
A number of in vitro studies have explored the potential role of carnosine in modulating elements of neurodegenerative disorders, especially the formation of β-amyloid fibrils as a pathological hallmark of Alzheimer’s disease (AD).
AD is the most common form of dementia and reflects progressive cognitive impairment sufficient to impact on activities of daily living .
Atomic force microscopy revealed that carnosine in a dose-dependent fashion reduced amyloid beta peptide 1-42 (Aβ1-42) polymerization and decreased the number of deposited aggregates in a model of the amyloidogenic peptide fragment Aβ1-42, which suggests that carnosine may inhibit Aβ1-42 fibrillogenesis.
Carnosine also significantly affected the structure of fibrils with predominance to short-sized fibrillar aggregates and reduced fibril growth . Another study extended these findings by showing that carnosine inhibited amyloid growth.
At 20-fold molar excess, carnosine reduced the aggregation of Aβ42 by 70% due to its interactions with the central hydrophobic area of β-amyloid, which plays an essential role in aggregation processes .
However, carnosine failed to modify the conformational features of Aβ42  or the pathology of tau protein, which is a protein that stabilizes microtubules that were found to be defective in AD .
Carnosine seems to be effective in protecting rat brain vascular endothelial cells (RBE4) against β-amyloid-induced cytotoxicity  and to inhibit lysozyme fibril formation-related cytotoxicity in human neuroblastoma SH-SY5Y cells .
Another important observation using this neuroblastoma cell model indicated that carnosine co-treatment (but not pretreatment) prevented serotonin-derived melanoid toxicity, which suggests that direct interaction of carnosine with the process of sevoflurane-induced sequestration of age-related acrolein lead to accumulation of serotonine derived melanoid and subsequent neuronal toxicity could be prevented by L-carnosine .
Carnosine also induced expression of the brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in a human primary glioblastoma cell line (but not neuroblastoma) . These neurotrophins and their signaling pathways play a critical role in neurodevelopment and adult brain plasticity, neuronal survival, differentiation and function, and repair mechanisms, and have been implicated in aging processes and the development of AD .
Another mechanism may be related to carnosine Cu2/Zn2+ chelating properties. Zn2+ and Cu2+ play a role in the pathogenesis of AD, since the interaction between β-amyloid and Cu2+ results in reactive oxygen species (ROS) formation and release of pre-synaptic Zn2+ from glutaminergic terminals, which, in turn, promotes formation of β-amyloid plaques .
Two in vitro studies showed that carnosine has inhibitory effects on β-amyloid aggregation and oxidative stress due to chelation of Cu2/Zn2+[48,54].
Another common neurodegenerative disorder is Parkinson’s disease (PD), which affects ~1% of the population aged more than 60 years . PD is caused by the loss of dopaminergic neurons, which leads to reduced control of smooth muscle and body movements and manifests as tremor, rigidity, and bradykinesia .
Only one study has explored the effects of carnosine on a cell model of PD. In this scenario, carnosine reduced apoptosis and mitochondria-derived production of ROS in brain endothelial cells and normalized the levels of lipid peroxidation (malondialdehyde, MDA) and anti-oxidant enzymes .
Major Depressive Disorder
Few cell studies have explored the role of carnosine in pathophysiological models of major depressive disorder (MDD), which is a severe and debilitating form of depression affecting approximately 5–20% of the worldwide population .
Recent meta-analyses showed a negative association between depression and telomere length  as well as between depression and the presence of metabolic syndrome .
Although limited, data from human and animal cell studies suggest that carnosine might have a potential to maintain telomere length  and delay cellular senescence  in fibroblasts, as well as ameliorate stress-induced changes in skeletal muscle and liver metabolism . These mechanisms are concordant with some of the beneficial effects of carnosine on depressive disorders .
Summary of Evidence from Cell Studies
For neurological disorders such as brain ischemia, evidence indicates that the neuroprotective and anti-ischemic effects of carnosine may be specific to cell type and include attenuation of astrogliosis, restoration of cell energetic balance, mitochondrial protection, and reversal of deleterious autophagic processes with a positive impact on the glutaminergic system.
Regarding neurodegenerative disorders, evidence from cell studies using in vitro models of AD and PD highlight the functional as well as structural anti-aggregating effects of carnosine in relation to early stage fibril formation, stimulation of neurogenesis in glial cells, and cyto-protection through ion chelation and anti-oxidation, which is likely to take place during cell differentiation.
These effects appear to be concentration-dependent and time-dependent . Lastly, cell studies in psychiatric disorders are scarce. Yet, despite indirect and limited evidence, some data support a role for carnosine in factors associated with MDD such as telomere length and cellular senescence, which are intriguing findings that require further