Is tau pathology a relevant factor in neuronal damage induced by alcohol and other drugs?

Unrestricted alcohol consumption and other substances like methamphetamine (ecstasy), opioids, cannabis, and cocaine have generated serious health concerns in the world population. The abusive use of these substances produces neuropathological alterations that could lead to cognitive decline and neurodegeneration. Pathological damage generated by these drugs resembles neurodegenerative changes observed in neurological disorders (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and others. One of the relevant elements distinguished in these diseases is the aggregation of intraneuronal proteins and deregulation of the neuronal cytoskeleton. In this context, the toxic modification of tau protein, a microtubule-associated protein (MAP), has raised new interest in drug and alcohol abuse research. Tau can undergo different pathological changes in which its anomalous phosphorylation and truncation state are relevant for NDs. These modifications produce a detachment from microtubule structures, affecting axonal transport and synaptic plasticity. Current studies suggest that alcohol and drug abuse may affect the mechanisms behind tau phosphorylation, inducing dysregulation of kinase/phosphatase activities and toxic tau accumulation. These alterations could be a key element that contributes to cognitive decline and neurodegeneration caused by substance abuse. Therefore, it is pivotal to understand how alcohol and other drugs contribute to neuronal damage by inducing tau pathology. This knowledge could generate new strategies and biomedical targets to reduce addictive consumption, neurodegeneration, and cognitive decline produced by substance abuse.