Tau phosphorylation is a multifaceted phenomenon characterized by the enzymatic attachment of phosphate groups to distinct serine, threonine, and tyrosine residues within the structural framework of the tau protein44. Aberrant phosphorylation of tau protein plays a pivotal role in the pathogenesis of Alzheimer’s condition. This pathological process ultimately culminates in the formation of tau aggregates and neurofibrillary tangles, which are closely associated with the progressive degeneration of neuronal structures and subsequent decline in cognitive function45,46.
Multiple kinases have been identified as key players in the process of tau phosphorylation. These kinases can be categorized into two main groups: proline-directed and non-proline-directed kinases39,44,47–51. Examples of proline-directed kinases involved in tau phosphorylation include glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinase 5 (CDK5). Non-proline-directed kinases such as microtubule affinity-regulating kinases (MARKs) and casein kinase 1 (CK1) have also been implicated in this phosphorylation process45,52–61. In addition to its well-established role as a microtubule-associated protein, tau is phosphorylated by various tyrosine kinases including Fyn, Abl, and Syk21,44,47,62. In contrast, it is noteworthy to consider the presence of tau dephosphorylation kinases, namely protein phosphatase-1, -2A, and -5 (PP1, PP2A, and PP5), which play pivotal roles in the dephosphorylation of tau by facilitating the removal of phosphate groups14,44,59,63–67.
Identification of phosphorylation events at specific sites, including Thr231, Ser199, and Tyr18, has been recognized as an initial event in the progression of Alzheimer’s disease (AD)45–48,50. As the pathological progression unfolds, there is a notable escalation in the process of phosphorylation at additional sites, namely Ser202/Thr205 and Ser42245. The accumulation of phosphorylated tau protein has been observed to have deleterious effects on microtubule dynamics, axonal transport, and synaptic function44,52,68–70. These disruptions ultimately contribute to synaptic dysfunction and the subsequent cellular loss15,71.
The presence of extensively phosphorylated tau species has consistently been linked to synaptic dysfunction and neurodegeneration in various studies33,39,71. Mitochondrial proteins can interact with external agents, resulting in disruption of mitochondrial function44,72,73. This in turn results in compromised energy metabolism in neurons74. The influence of phosphorylated tau on the distribution of mitochondria within neurons and its impact on axonal transport have been well documented in the literature5,44,75.
In the context of Alzheimer’s disease (AD) pathogenesis, it is widely acknowledged that tau phosphorylation plays a pivotal role in the pathogenesis of AD44,76,77. Consequently, there is growing interest in investigating the therapeutic potential of targeting tau kinases or phosphatases as a means to address the underlying mechanisms of AD39,44,78,79. Comprehending the complexities inherent in the process of tau phosphorylation is of paramount significance in the pursuit of formulating efficacious therapeutic interventions aimed at impeding or decelerating the progression of this profound neurodegenerative disorder.
Accordingly, many progresses have been established in formulating compounds that directly inhibit tau phosphorylation. For example, the Cdk5 inhibitory peptide hinders tau hyperphosphorylation by disrupting the formation of the cdk5/p25 complex. Riscovitine, a cdk5 inhibitor, has also been found effective in reducing tau hyperphosphorylation and neurodegeneration. In vitro studies with lithium, a GSK3 inhibitor, have shown to inhibit tau phosphorylation, limit tau aggregation, mitigate neuronal degradation, and facilitate microtubule assembly. Similarly, GSK3 inhibitory compounds such as AR-A014418 and NP-12, have been successful in decreasing insoluble tau levels, preventing tau aggregation, downregulating tau phosphorylation, and reducing concentrations of amyloid plaques in mouse models. Furthermore, these results have been found to also mitigate neuronal death in the entorhinal cortices and hippocampus and enhance memory deficits in mouse brains. Other studies have found that the K252a compound, a serine/threonine protein kinase inhibitor, has proved useful in blocking tau hyperphosphorylation in rat brain cells. Although the aforementioned compounds have been found to be effective in limiting tau phosphorylation for applications in AD treatment, limitations such as low bioaccumulation, insignificant in vivo circulation times, and non-specific targeting abilities have restricted the effectiveness of these therapeutic compounds. Perhaps synergizing these anti-phosphorylation compounds with nanoparticles can overcome these limitations and offer a more effective therapeutic for hyperphosphorylation-driven AD manifestations. The prospects of integrating nanoparticles in tau-targeted therapies will be further explored in later sections of this paper.