This review explores the proposed mechanisms of tau in traumatic brain injury (TBI), Alzheimer's disease (AD), and epilepsy, focusing on its role in neuronal injury, inflammation, and neurodegeneration. Tau is a neuronal protein involved in maintaining axonal transport and microtubule stability. Under normal conditions, tau is intracellular, but in tauopathies, phosphorylated (p-) and hyper-phosphorylated (hp-) tau are released extracellularly, leading to neurofibrillary tangles (NFTs) and neuronal dysfunction. Tau cleavage by caspases increases susceptibility to hyperphosphorylation and NFT formation, contributing to cell death. The relationship between tau and inflammation is unclear, but imbalanced endoplasmic reticulum (ER) stress and inflammatory signaling pathways are proposed to result in atypical p-tau and hp-tau, as well as NFT formation. In TBI, AD, and epilepsy, tau phosphorylation is proposed as an initial acute neuroprotective response to seizures or injury. However, if the underlying pathology is not effectively treated, the pathway becomes chronically activated, leading to a "tipping point" where tau phosphorylation transitions from neuroprotective to injurious. Amyloid-beta (Aβ) is proposed as a "last ditch effort" to revert the cell to programmed death signaling, but if this fails, it transitions the mechanism to neurodegeneration. The review outlines the role of Aβ in promoting tau cleavage and hyperphosphorylation, contributing to neurodegenerative processes. It also discusses the role of inflammatory signaling, ER stress, and the balance between excitatory and inhibitory neurotransmission in these conditions. The review proposes that tau plays a key role in neuroprotection, but chronic or sustained activation of tau signaling pathways can lead to neurodegeneration. The interplay between tau, Aβ, and inflammatory signaling pathways is complex and contributes to the progression of TBI, AD, and epilepsy.This review explores the proposed mechanisms of tau in traumatic brain injury (TBI), Alzheimer's disease (AD), and epilepsy, focusing on its role in neuronal injury, inflammation, and neurodegeneration. Tau is a neuronal protein involved in maintaining axonal transport and microtubule stability. Under normal conditions, tau is intracellular, but in tauopathies, phosphorylated (p-) and hyper-phosphorylated (hp-) tau are released extracellularly, leading to neurofibrillary tangles (NFTs) and neuronal dysfunction. Tau cleavage by caspases increases susceptibility to hyperphosphorylation and NFT formation, contributing to cell death. The relationship between tau and inflammation is unclear, but imbalanced endoplasmic reticulum (ER) stress and inflammatory signaling pathways are proposed to result in atypical p-tau and hp-tau, as well as NFT formation. In TBI, AD, and epilepsy, tau phosphorylation is proposed as an initial acute neuroprotective response to seizures or injury. However, if the underlying pathology is not effectively treated, the pathway becomes chronically activated, leading to a "tipping point" where tau phosphorylation transitions from neuroprotective to injurious. Amyloid-beta (Aβ) is proposed as a "last ditch effort" to revert the cell to programmed death signaling, but if this fails, it transitions the mechanism to neurodegeneration. The review outlines the role of Aβ in promoting tau cleavage and hyperphosphorylation, contributing to neurodegenerative processes. It also discusses the role of inflammatory signaling, ER stress, and the balance between excitatory and inhibitory neurotransmission in these conditions. The review proposes that tau plays a key role in neuroprotection, but chronic or sustained activation of tau signaling pathways can lead to neurodegeneration. The interplay between tau, Aβ, and inflammatory signaling pathways is complex and contributes to the progression of TBI, AD, and epilepsy.