Proposed mechanisms of tau: relationships to traumatic brain injury, Alzheimer’s disease, and epilepsy

Abstract

Traumatic brain injury (TBI), Alzheimer’s disease (AD), and epilepsy share proposed mechanisms of injury, including neuronal excitotoxicity, cascade signaling, and activation of protein biomarkers such as tau. Although tau is typically present intracellularly, in tauopathies, phosphorylated (p-) and hyper-phosphorylated (hp-) tau are released extracellularly, the latter leading to decreased neuronal stability and neurofibrillary tangles (NFTs). Tau cleavage at particular sites increases susceptibility to hyper-phosphorylation, NFT formation, and eventual cell death. The relationship between tau and inflammation, however, is unknown. In this review, we present evidence for an imbalanced endoplasmic reticulum (ER) stress response and inflammatory signaling pathways resulting in atypical p-tau, hp-tau and NFT formation. Further, we propose tau as a biomarker for neuronal injury severity in TBI, AD, and epilepsy. We present a hypothesis of tau phosphorylation as an initial acute neuroprotective response to seizures/TBI. However, if the underlying seizure pathology or TBI recurrence is not effectively treated, and the pathway becomes chronically activated, we propose a “tipping point” hypothesis that identifies a transition of tau phosphorylation from neuroprotective to injurious. We outline the role of amyloid beta (Aβ) as a “last ditch effort” to revert the cell to programmed death signaling, that, when fails, transitions the mechanism from injurious to neurodegenerative. Lastly, we discuss targets along these pathways for therapeutic intervention in AD, TBI, and epilepsy.

Understanding epileptogenesis from molecules to network alteration

“…A recent study has found higher levels of tau and amyloid-β accumulation in the surgical specimens of drug-resistant epilepsy [ 27 , 28 ], indicating that tau and amyloid-β participate in the pathogenesis of epilepsy and are not merely byproducts of the degenerative process. This can be explained by glutamate toxicity between phosphorylated tau, amyloid-β, and seizures [ 29 ]. Amyloid-β increases glutamate secretion at synapses, leading to an increase in N -methyl-ᴅ-aspartate (NMDA)-mediated intracellular calcium, which induces an increase in extracellular amyloid.…”