Repetitive mild TBI causes pTau aggregation in nigra without altering preexisting fibril induced Parkinson’s-like pathology burden

Abstract

Population studies have shown that traumatic brain injury (TBI) is associated with an increased risk for Parkinson’s disease (PD) and among U.S. Veterans with a history of TBI this risk is 56% higher. The most common type of TBI is mild (mTBI) and often occurs repeatedly among athletes, military personnel, and victims of domestic violence. PD is classically characterized by deficits in fine motor movement control resulting from progressive neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) midbrain region. This neurodegeneration is preceded by the predictable spread of characteristic alpha synuclein (αSyn) protein inclusions. Whether repetitive mTBI (r-mTBI) can nucleate PD pathology or accelerate prodromal PD pathology remains unknown. To answer this question, an injury device was constructed to deliver a surgery-free r-mTBI to rats and human-like PD pathology was induced by intracranial injection of recombinant αSyn preformed fibrils. At the 3-month endpoint, the r-mTBI caused encephalomalacia throughout the brain reminiscent of neuroimaging findings in patients with a history of mTBI, accompanied by astrocyte expansion and microglial activation. The pathology associated most closely with PD, which includes dopaminergic neurodegeneration in the SNpc and Lewy body-like αSyn inclusion burden in the surviving neurons, was not produced de novo by r-mTBI nor was the fibril induced preexisting pathology accelerated. r-mTBI did however cause aggregation of phosphorylated Tau (pTau) protein in nigra of rats with and without preexisting PD-like pathology. pTau aggregation was also found to colocalize with PFF induced αSyn pathology without r-mTBI. These findings suggest that r-mTBI induced pTau aggregate deposition in dopaminergic neurons may create an environment conducive to αSyn pathology nucleation and may add to preexisting proteinaceous aggregate burden.

Systematic Review of Post-Traumatic Parkinsonism, an Emerging Parkinsonian Disorder Among Survivors of Traumatic Brain Injury

“…We have found in pre-clinical rat models of α-Syn fibril-induced PD that pTau is localized in Lewy bodies (LBs) within dopaminergic neurons. 22 Similarly, we also found pTau aggregates within dopaminergic neurons of rats that underwent repetitive mild TBI. 22 If PTP induces pTau aggregation in surviving dopaminergic neurons, it could predispose cells to development of PD-specific proteinopathy by cross-seeding aggregation of α-Syn into LBs and Lewy neurites.…”

“… 22 Similarly, we also found pTau aggregates within dopaminergic neurons of rats that underwent repetitive mild TBI. 22 If PTP induces pTau aggregation in surviving dopaminergic neurons, it could predispose cells to development of PD-specific proteinopathy by cross-seeding aggregation of α-Syn into LBs and Lewy neurites. Similarly, pTau-targeted therapeutics developed for Alzheimer's disease could potentially be used to limit or slow the progression of PTP to PD.…”

Substantia Nigra Pathology, Contact Sports Play, and Parkinsonism in Chronic Traumatic Encephalopathy

“…We observed that years of contact sports participation and SN neuronal loss were associated with nigral NFTs, which were nearly twice as common as LBs in individuals with parkinsonism, and that SN neuronal loss, in turn, was associated with parkinsonism. The SN is involved early in CTE and accumulates a high p-tau burden as the disease progresses, including a concomitant loss of nigral neuromelanin-containing neurons that can be noted macroscopically at autopsy, and animal modeling has likewise demonstrated nigral p-tau following RHI . These findings together indicate nigral susceptibility to damage and degeneration following head injury.…”

“…The SN is involved early in CTE and accumulates a high p-tau burden as the disease progresses, 7,8 including a concomitant loss of nigral neuromelanin-containing neurons that can be noted macroscopically at autopsy, and animal modeling has likewise demonstrated nigral p-tau following RHI. 59 These findings together indicate nigral susceptibility to damage and degeneration following head injury.…”