Substance Abuse and Cognitive Decline: The Critical Role of Tau Protein as a Potential Biomarker

Abstract

Tau protein is essential for the structural stability of neurons, particularly through its role in microtubule assembly and axonal transport. However, when abnormally hyperphosphorylated or cleaved, Tau can aggregate into insoluble forms that disrupt neuronal function, contributing to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Emerging evidence suggests that similar Tau-related alterations may occur in individuals with chronic exposure to psychoactive substances. This review compiles experimental, clinical, and postmortem findings that collectively indicate a substance-specific influence on Tau dynamics. Alcohol and opioids, for instance, promote Tau hyperphosphorylation and fragmentation through the activation of kinases such as GSK-3β and CDK5, as well as proteases like caspase-3, leading to neuroinflammation and microglial activation. Stimulants and dissociatives disrupt insulin signaling, increase oxidative stress, and impair endosomal trafficking, all of which can exacerbate Tau pathology. In contrast, cannabinoids and psychedelics may exert protective effects by modulating kinase activity, reducing inflammation, or enhancing neuroplasticity. Psychedelic compounds such as psilocybin and harmine have been demonstrated to decrease Tau phosphorylation and facilitate cognitive restoration in animal models. Although the molecular mechanisms differ across substances, Tau consistently emerges as a convergent target altered in substance-related cognitive disorders. Understanding these pathways may provide not only mechanistic insights into drug-induced neurotoxicity but also identify Tau as a valuable biomarker and potential therapeutic target for the prevention or treatment of cognitive decline associated with substance use.

Keywords: Tau protein; cognitive dysfunction; neurodegeneration; p-Tau; substance abuse.

Figure 1

PRISMA flow diagram of the search and selection process.

Figure 2

Schematic representation of the molecular mechanisms by which alcohol (a depressant) contributes to Tau pathology and cognitive impairment. Alcohol promotes Tau phosphorylation (p-Tau) via activation of Caspase-3 and GSK-3β, leading to Tau cleavage and the formation of C-terminal Tau fragments. Additionally, alcohol inhibits several key cellular pathways—PP2A, Klotho, TREM2, and LAMP1—which are typically involved in Tau dephosphorylation, antioxidant defense, microglial clearance, and autophagy, respectively. Dysregulation of these pathways contributes to Tau accumulation, aggregation, and impaired degradation, ultimately leading to cognitive dysfunction. Abbreviations and symbols: p-Tau: phosphorylated Tau; C-Tau: C-terminal Tau fragments; GSK-3β: glycogen synthase kinase-3 beta; PP2A: protein phosphatase 2A; mTOR: mechanistic target of rapamycin; TREM2: triggering receptor expressed on myeloid cells 2; APOE: apolipoprotein E; LAMP1: lysosomal-associated membrane protein 1; Klotho: longevity-associated protein; ↑: increase; ↓: decrease; →: leads to. Figure created with BioRender.com.

Figure 3

Effects of stimulants (cocaine and methamphetamine) on Tau phosphorylation and related molecular pathways. The image illustrates how exposure to stimulants such as cocaine and methamphetamine promotes Tau phosphorylation and neurotoxicity through various molecular mechanisms. Key pathways include GSK-3β and CDK5 activation, Fyn kinase-mediated NMDA receptor activation, and impaired autophagy via Stx17. Inhibition of insulin signaling pathways (AKT/IRS-1 and PI3K/AKT) further contributes to GSK-3β hyperactivation and p-Tau accumulation. These events lead to Tau cleavage, aggregation, cytoskeletal dysfunction, and synaptic toxicity, ultimately associated with cognitive impairment. Abbreviations and symbols: GSK-3β: glycogen synthase kinase-3 beta; CDK5: cyclin-dependent kinase 5; Fyn: non-receptor Src family tyrosine kinase; NMDA: N-methyl-D-aspartate; PERK: protein kinase RNA-like endoplasmic reticulum kinase; caspase-12: cysteine-aspartic protease 12; α-synuclein: alpha-synuclein; IRS-1: insulin receptor substrate-1; AKT: protein kinase B; Stx17: syntaxin 17; PI3K: phosphoinositide 3-kinase; p-Tau: phosphorylated Tau; ↑: increase; ↓: decrease; →: leads to. Figure created with BioRender.com.

Figure 4

Neuroprotective effects of cannabinoids on Tau pathology. This diagram illustrates the molecular pathways through which cannabinoids reduce Tau phosphorylation and neurotoxicity. Cannabinoids activate AMPK and CB1/CB2 receptors, which in turn enhance Wnt/β-catenin signaling and inhibit GSK-3β activity. These interactions result in decreased p-Tau levels and reduced neurotoxicity. The green arrows indicate promotion, while the red lines indicate inhibition. Abbreviations and symbols: AMPK: AMP-activated protein kinase; CB1/CB2: cannabinoid receptor type 1 and type 2; Wnt: Wingless-related integration site; β-catenin: beta-catenin; GSK-3β: glycogen synthase kinase-3 beta; p-Tau: phosphorylated Tau; ↓: decrease; →: leads to. Figure created with BioRender.com.

Figure 5

Mechanisms of opioid-induced Tau pathology. The diagram summarizes the molecular pathways by which opioids promote Tau hyperphosphorylation and neurotoxicity. Opioid exposure enhances the activity of kinases such as GSK-3β, CDK5/p35, and JNK/p38 MAPK, leading to increased Tau phosphorylation. Additionally, PKC-induced phosphorylation of KEPI inhibits PP1, a phosphatase responsible for Tau dephosphorylation, resulting in p-Tau accumulation. Overall, this contributes to cytoskeletal disruption and neuronal damage. Green arrows indicate promotion; red lines indicate inhibition. Abbreviations and symbols: GSK-3β: glycogen synthase kinase-3 beta; CDK5/p35: cyclin-dependent kinase 5 with its activator p35; JNK/p38 MAPK: c-Jun N-terminal kinase/p38 mitogen-activated protein kinase; KEPI: kinase enhanced phosphatase inhibitor; PKC: protein kinase C; PP1: protein phosphatase 1; p-Tau: phosphorylated Tau; ↑: increase; ↓: decrease; →: leads to. Figure created with BioRender.com.

Figure 6

Dissociative drugs and their effects on Tau phosphorylation and neurotoxicity pathways. This figure illustrates the mechanisms through which dissociative drugs modulate Tau pathology. Inhibitory effects on AMPAR and NMDA receptors lead to decreased synaptic plasticity and calcium influx, promoting Tau hyperphosphorylation and neurotoxicity. Simultaneously, activation of downstream kinases such as CaMKII, MARK, ERK, and GSK-3β promotes Tau phosphorylation, while impaired Rab5/Rab7-mediated endo-lysosomal degradation contributes to p-Tau accumulation. Green arrows indicate promotion, and red lines indicate inhibition of the indicated process. Abbreviations and symbols: AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; NMDA: N-methyl-D-aspartate receptor; CaMKII: calcium/calmodulin-dependent protein kinase II; MARK: microtubule affinity-regulating kinase; ERK: extracellular signal-regulated kinase; GSK-3β: glycogen synthase kinase-3 beta; Rab5/Rab7: Ras-related proteins involved in endosomal trafficking; p-Tau: phosphorylated Tau; Ca²⁺: calcium ion; ↑: increase; ↓: decrease; →: leads to. Figure created with BioRender.com.

Figure 7

Psychedelics and their dual regulatory role in Tau phosphorylation pathways. This diagram illustrates how psychedelics influence Tau phosphorylation through both neuroprotective and neurotoxic pathways. Activation of BDNF-TrkB signaling reduces Tau phosphorylation by modulating PI3K/AKT and MAPK/ERK pathways, which inhibit GSK-3β, ultimately decreasing neurotoxicity. Conversely, psychedelics also inhibit DYRK1A, a kinase that typically promotes Tau phosphorylation at Thr212 and Ser396, leading to reduced aggregation and neurotoxicity. Green arrows indicate promotion, and red lines indicate inhibition. Abbreviations and symbols: BDNF: brain-derived neurotrophic factor; TrkB: tropomyosin receptor kinase B; PI3K/AKT: phosphoinositide 3-kinase/protein kinase B pathway; MAPK/ERK: mitogen-activated protein kinase/extracellular signal-regulated kinase; GSK-3β: glycogen synthase kinase-3 beta; DYRK1A: dual-specificity tyrosine-phosphorylation-regulated kinase 1A; p-Tau: phosphorylated Tau; ↓ decrease; →: leads to. Figure created with BioRender.com.