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Advanced Neurology EPAC2 null leads to tauopathy

A single-nucleotide polymorphism in the EPAC2 gene, an important role of CDK5 in tau pathology (Figure 7).
rs17746510, which is adjacent to the catalytic domain Notably, CDK5 is a pro-apoptotic factor, especially in the
sequence, is associated with cognitive decline, apathy, and contexts of neurotoxicity, oxidative stress, and Aβ oligomer
mood disturbance in Chinese AD patients . Consistent stimulation . Moreover, activation of CDK5 leads to the
[7]
[38]
with this finding, EPAC2 mice exhibit emotional inactivation of peroxiredoxins I and II, two important
−/−
perturbations, including anxiety, and depression , as seen reactive oxygen species (ROS) scavengers, resulting in the
[7]
[24]
in the early stages of AD in humans . The reduction in accumulation of ROS in neurons and mitochondrial damage.
EPAC2 is particularly notable in the frontal cortex and In line with this, hyperphosphorylated tau also induced
hippocampus, the two most severely affected brain areas in mitochondrial dysfunction both in vitro and in vivo. In
AD, but not in resistant regions such as the cerebellum . addition, CDK5 can directly phosphorylate APP at Thr668
[8]
In our previous study, we found that EPAC2 was decreased to increase Aβ secretion , and indirectly facilitate Aβ
[39]
in rats with scopolamine-induced short-term amnesia, production by promoting Golgi fragmentation . Finally,
[40]
an animal model of dementia . Loss of EPAC2 results CDK5 activation can cause disruption to the dendritic
[25]
in the over-stabilization of excitatory synapses and an spines and dendritic morphology by impacting numerous
increase in inhibitory input onto neurons, leading to an downstream substrates. Therefore, targeting CDK5 might
imbalance in excitatory/inhibitory synapses , which is an be a promising therapeutic approach for AD.
[26]
important synaptic phenotype in AD . Moreover, a rare −/−
[27]
missense mutation in EPAC2, V646F-EPAC2, mimics the We noticed that for the activation of CDK5 in EPAC2
effect of EPAC2 knockdown, with reduced GEF activity mice, calpain activity was crucial. As reported, an
and perturbed dendritic spines , which is one of the upregulation of calpain activity is found in both AD animal
[28]
[41,42]
most important post-synaptic compartments severely models and human postmortem brains . In addition,
affected in AD . In this study, we identified aberrant tau calpain activation plays a very important role in neuronal
[29]
hyperphosphorylation at multiple sites. It is known that loss (necrosis and apoptosis) in AD, as shown by many
[43]
tau hyperphosphorylation is one of the key pathological in vitro and in vivo studies . Moreover, calpain is activated
hallmarks of AD . Hyperphosphorylated tau is highly by Aβ exposure, resulting in the dysregulation of brain-
[2]
correlated with the synaptic disorder in AD. For example, derived neurotrophic factor signaling, which might lead
[44]
hyperphosphorylation of tau reduces its binding affinity to the synaptic disorder in AD . Furthermore, in an AD
for microtubules, causing it to detach and mislocalize mouse model, calpain activation is suggested to promote
[45]
to the dendritic compartment [11,30] . Furthermore, Aβ generation, which may form a vicious cycle . Here,
−/−
hyperphosphorylated tau can immobilize synaptic blocking the activation of calpain in the EPAC2 mice
vesicles by preventing their release from F-actin . In robustly reduced tau hyperphosphorylation and CDK5
[31]
many tau mutant and transgenic models, dysregulation activation. In some previous reports, the upregulation of
of the synaptic proteome, impaired synaptic plasticity, calpain activity was found to generate a toxic tau fragment
[46]
and a reduction in synapses and dendritic spines are in hippocampal neurons . Together, the lines of evidence
found . Thus, it is possible that the EPAC2 loss-induced strongly suggest a critical role of calpain in tau pathology
[32]
tau hyperphosphorylation plays an important role in the in AD. However, further study is needed to elucidate
synaptic dysfunction in AD. whether calpain activation plays a direct or indirect role in
tau hyperphosphorylation in EPAC2 mice.
−/−
We also found here that CDK5 activation is the
principal event involved in tau hyperphosphorylation in 5. Conclusion
EPAC2 mice. It is known that CDK5 activation induces
−/−
the phosphorylation of tau at Thr181, Ser199, Ser202, The current findings collectively provide strong evidence
Thr205, Thr212, Ser214, Thr217, Thr231, Ser235, Ser396, for a critical role of EPAC2 in tau pathology and provide
and Ser404, which are sites that are critical in the formation insight into the underlying signaling pathways.
of NFTs in AD [1,33] . CDK5 is upregulated in neurons Acknowledgments
containing NFTs . Numerous studies have revealed a
[34]
positive correlation between CDK5 activation and NFTs This study was partially supported by the National Natural
in AD brains [33,35] . Directly blocking CDK5 activity or Science Foundation of China (82030032, 81961128005,
the cleavage of p35 to p25 in cultured neurons effectively 81901103, 81829002, 81871108, and 31721002), the
suppresses tau hyperphosphorylation [36,37] . In our present National Key Research and Development Program of
study, administration of roscovitine, a specific inhibitor of China (Grant No. 2019YFE0121200), and Top-Notch
CDK5, not only attenuated the tau hyperphosphorylation Young Talents Program of China of 2014 to Dr. Ling-
but also reduced tau aggregation. These findings suggest Qiang Zhu.

Volume 1 Issue 1 (2022) 9 https://doi.org/10.36922/an.v1i1.8