Military personnel in the battlefield and athletes in contact sports including boxing and American football [5, 6] [7] [8] [9] [10] [11] [12] are exposed to mild repetitive TBI, which can result in chronic traumatic encephalopathy (CTE)

Military personnel in the battlefield and athletes in contact sports including boxing and American football [5, 6] [7] [8] [9] [10] [11] [12] are exposed to mild repetitive TBI, which can result in chronic traumatic encephalopathy (CTE). in pretangle (phosphorylated pS422) and oligomeric (TOC1 and TNT1) forms of tau in stage IV compared to stage II CTE cases. The nbM neurons also displayed pathologic TDP-43 inclusions and diffuse extracellular and vascular amyloid- (A) deposits in CTE. A higher percent of pS422/p75NTR, pS422 and TNT1 labeled neurons were significantly correlated with age at symptom onset, interval between symptom onset and death and age at death. Conclusion The development of NFTs within the nbM neurons could contribute to the basal forebrain cortical cholinergic disconnection in CTE. Further studies are needed to determine the mechanism driving NFT formation in the nbM neurons and its relation to chronic cognitive dysfunction in CTE. strong class=”kwd-title” Keywords: cognition, head injury, memory, mild brain injury, traumatic brain injury Introduction Traumatic brain injury (TBI) is the signature wound Lauric Acid of recent military conflicts, with 20% of U.S. service men and women sustaining at least one head injury, mainly mild TBI [1, 2]. TBI is associated with onset of long-term behavioral and cognitive problems [3] [4], but the underlying neurobiological mechanisms remain unclear. Military personnel in the battlefield and athletes in contact sports including boxing and American football [5, 6] [7] [8] [9] [10] [11] [12] are exposed to mild repetitive TBI, which can result in chronic traumatic encephalopathy (CTE). The neuropathology of CTE is characterized by intracellular accumulation of abnormally phosphorylated tau protein (p-tau), the main constituent of neurofibrillary tangles (NFT) in Alzheimers disease (AD) and non-AD tauopathies [13]. While neuropathological investigations have demonstrated extensive cortical damage in CTE [14], the potential involvement of subcortical neurotransmitter systems is poorly understood. Among the subcortical systems displaying NFTs in AD are cholinergic neurons of the basal forebrain which provide the major acetylcholine (Ach) innervation to the cortical mantle and hippocampus and are involved in memory and cognitive functions [15] [16] [17, 18]. The cholinergic neurons within the basal forebrain are contained within several subfields extending rostrally from the septal diagonal band throughout the nucleus basalis of Meynert (nbM), caudally [18] [9]. Degenerative changes in the cortical-projecting cholinergic neurons are known to contribute to the cognitive and attentional deficits seen in AD [19] [20]. Several clinical pathological investigations report that similar pathology can develop chronically after TBI [21]. For example, the cerebral cortex of individuals who died as a consequence of head injury display reduced activity of the synthetic enzyme for Ach, choline acetyltransferase (ChAT), as well as STMY morphological alterations and reduced ChAT immunoreactivity of the cholinergic nbM neurons [22]. TBI is also associated with acute down-regulation of the vesicular Ach transporter (VAChT, the regulator of Ach neurotransmission) and acetylcholinesterase (AChE, the Ach-degrading enzyme) [23] [24]. Moreover, several studies indicated that donepezil, an AChE inhibitor, improves cognitive function and attention after TBI [25], although this remains controversial [26] [27] [28]. The mechanism(s) driving cholinergic nbM neuronal dysfunction following CTE remain unknown. It is possible that these neurons undergo alterations of their survival protein, nerve growth factor [29, 30], which is retrogradely transported from the cortex to the nbM cholinergic neurons through a complex interaction with its two cognate receptors, the high-affinity NGF-specific cell survival tyrosine kinase (trkA) and the putative cell death associated low-affinity pan neurotrophin (p75NTR) receptor [31] [32]. In Lauric Acid AD, these neurons also develop intracellular lesions that appear as globose p-tau-positive NFTs [33] [13]. Tau is a microtubule-associated protein involved in normal cytoskeleton function [34] [35] and tau containing NFT pathology co-occurs within nbM neurons containing the cholinergic cell markers ChAT and p75NTR early in the onset of AD [36]. Recently, a linear model for NFT evolution has been proposed, that can be observed by antibodies directed against p-tau epitopes marking early, Lauric Acid intermediate, and.