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.