Originally Posted on Science Direct | 19 February 2017
Neurodegenerative diseases are characterized by distinctive neuropathological alterations, including the cerebral accumulation of misfolded protein aggregates, neuroinﬂammation, synaptic dysfunction, and neuronal loss, along with behavioral impairments. Tramaic brain injury (TBI) is believed to be an important risk factor for certain neurodegenerative diseases, such as Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE); Amyloid-beta and Tau Pathology follows repetitive mild TBI.
TBI represents a ubiquitous problem in the world and could play a major role in the pathogenesis and etiology of AD or CTE later in life. TBI events appear to trigger and exacerbate some of the pathological processes in these diseases, in particular, the formation and accumulation of misfolded protein aggregates composed of amyloid-beta (ab) and tau. Here, we describe the relationship between repetitive mild TBI and the development of Ab and tau pathology in patients affected by AD or CTE on the basis of epidemiological and pathological studies in human cases, and a thorough overview of data obtained in experimental animal models.
We also discuss the possibility that TBI may contribute to initiate the formation of misfolded oligomeric species that may subsequently spread the pathology through a prion-like process of seeding of protein misfolding.
The National Head Injury Foundation deﬁnes traumatic brain injury (TBI) as an “insult to the brain caused by an external force that may produce diminished or altered states of consciousness, which results in impaired cognitive abilities or physical functioning”. The World Health Organization estimates that 10 million people in the world are affected by TBI per year, speciﬁcally costing Americans $57 billion. TBI is the leading cause of death or disability noted in industrialized cities as well as in children and young adults. TBI reduces life expectancy by 7 years.
Mild TBI (mTBI) is acknowledged as head insults that cause a brief state of altered consciousness resulting 30 min of unconsciousness, yet most mTBIs do not result in loss of consciousness. The consequences of repetitive mild TBI (rmTBI) is a popular topic in research due to the fact that war veterans and contact sports athletes (i.e. American football, boxing, hockey, soccer, etc.) with TBI experiences are linked with a recently deﬁned disease: chronic traumatic encephalopathy (CTE), formerly termed dementia pugilistica.
Though the particular type of lesions resulting from mTBI are highly variable, various factors may play an important role in the consequences of the impact, including rotational acceleration and deceleration forces, ﬂuidic pulses from the lateral ventricles generating shearing forces, blow location, among others.
Athletes and soldiers having CTE display an overlapping and broad range of abnormal behaviors emerging mid-life that ultimately result in psychological issues that lead to violence and/or suicide. Following a primary TBI insult a multitude of secondary mechanisms take effect causing cytopathogenesis and neurological changes within the brain, as indicated by an association with neurodegenerative diseases, cognitive struggles, seizures, sleep disorders, neuroendocrine disorders, and other complications.
These secondary mechanisms involve excitotoxicity, Ca2þ overload, mitochondrial dysfunction, reactive oxygen species, and inﬂammation. These cellular and biochemical alterations lead to synaptic dysfunction, axonal degeneration, and neuronal death; thereby, initiating cognitive impairments. Interestingly, autopsy brain samples from CTE-diagnosed athletes and military veterans and others afﬁliated with some form of TBI, from teen ages to 80’s, display massive accumulation of misfolded protein aggregates, mainly composed of tau and amyloid-beta (Ab).
Tau and Ab inclusions are mostly known for their association with Alzheimer’s disease (AD), which is the most common form of dementia affecting elderly individuals. Neuroﬁbrillary tangles (NFTs) are formed by aggregates of hyper-phosphorylated tau protein (pTau). Tau is a microtubule associated protein that has six isoforms differing by 3R or 4R binding repeats. Tau plays an important role in axonal stabilization, neuronal development, and neuronal polarity. Ab is a 38e43 amino acid peptide produced by the cleavage of the amyloid precursor protein (APP) by b- and g-secretase. Under pathological conditions these proteins misfold and aggregate forming long ﬁbrillar polymers, which bind amyloid dies (e.g Thioﬂavin S and Congo red), and have a high resistance to cellular proteolytic degradation.
Related Articles on Brain Disorders:
- In Vivo Spreading of Tau Pathology
- The Role Of Protein Misfolding in Neurodegenerative Diseases
- Accurate CJD Diagnosis & Prevention of Disease Transmission
- Amyloid-b Deposition in Alzheimer’s Disease
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