Tadalafil and bergapten mitigate streptozotocin-induced sporadic Alzheimer's disease in mice via modulating neuroinflammation, PI3K/Akt, Wnt/β-catenin, AMPK/mTOR signaling pathways
Graphical abstract
Introduction
Sporadic Alzheimer's disease (SAD) is the most dominant form of dementia (Sabogal-Guáqueta et al., 2020). Its pathology is multifactorial and involves the accumulation of hyperphosphorylated tau proteins (pTau) with subsequent formation of neurofibrillary tangles (NFTs), deposition of amyloid beta (Aβ) plaques and neurodegeneration (Takahashi et al., 2017). Activation of phosphatidylinositol 3-kinase (PI3K) through growth factors including insulin, promotes cell survival and synaptic plasticity (Kamat et al., 2016). PI3K inhibits the downstream kinase, glycogen kinase-3β (GSK-3β) with subsequent reduction in pTau and Aβ levels (Kamat et al., 2016). GSK-3β is also thought to mediate neuroinflammation through the positive regulation of tumor necrosis factor-α (TNFα) and nuclear factor kappa B (NF-κB) (Najem et al., 2014).
Several upstream signals such as, insulin, PI3K/protein kinase-B (Akt), 5-adenosine monophosphate-activated protein kinase (AMPK), GSK-3β and protein phosphatase 2A (PP2A) can interact with the mammalian target of rapamycin (mTOR) (Querfurth and Lee, 2021) to induce hyperphosphorylation of Tau and generation of Aβ plaques. Previous studies have shown that mTOR hyperactivation can minimize autophagy and contribute directly to Tau hyperphosphorylation and aggregation (Kou et al., 2019; Mueed et al., 2018). Moreover, the levels of inflammatory mediators are correlated with the expression of the key autophagy regulators namely; mTOR and Beclin1 (Uddin et al., 2018). In addition, severe inflammation is directly linked to disrupted autophagic process in the microglia (Houtman et al., 2019).
Another important pathway implicated in the development of SAD is the canonical Wingless-related integration site (Wnt)/β-catenin (Tapia-Rojas and Inestrosa, 2018). Accumulation of Aβ stimulates the activation of Dickkopf-1 (Dkk1), the Wnt pathway inhibitor, and promotes the degradation of cytosolic β-catenin by GSK-3β, thus inhibiting its nuclear translocation, which is crucial for neuronal survival, neurogenesis and synaptic plasticity (Jia et al., 2019). As well, reduced Wnt signaling contributes to Tau hyperphosphorylation and promotes the processing of the amyloid precursor protein (APP) with increased production of Aβ through reduction of PI3K/Akt signaling (Palomer et al., 2019). Moreover, Wnt/β-catenin shutdown is associated with neuroinflammation and increased transcription of proinflammatory genes with the activation of the microglia and astrocytes (Vallée et al., 2017). Hence, modulation of the crosstalk between neuroinflammation, autophagy, impaired insulin and Wnt/β-catenin signaling can offer new approaches to treat SAD.
Coumarins, a group of naturally occurring secondary metabolites, were found to lower blood glucose levels and increase insulin sensitivity by enhancing glucose uptake through activation of the PI3K and AMPK signaling in vitro (Jang et al., 2020). The furanocoumarin, bergapten (BG; 5-methoxypsoralen) found in a variety of medicinal plants, has been demonstrated to have antidepressant (Budzynska et al., 2016), anti-oxidant (Kowalczyk et al., 2020), and anti-inflammatory effects (Adakudugu et al., 2020). Administration of BG was further found to significantly inhibit proinflammatory cytokines (Singh et al., 2019).
Phosphodiesterase 5-inhibitors (PDE5-Is) such as tadalafil (TAD) were reported to alleviate cognitive deficits by reducing neuroinflammation and Aβ deposition (França et al., 2019; García-barroso et al., 2013; Zhang et al., 2013). Cyclic nucleotides including cyclic guanosine monophosphate (cGMP) play important role in neuroplasticity and memory formation (Argyrousi et al., 2020). Several studies showed that PDE5-Is regulate the transcription of the brain-derived neurotrophic factor (BDNF) (Cuadrado-Tejedor et al., 2011; Rosa and Fahnestock, 2015).
Accordingly, the current study aimed at investigating the possible neuroprotective potential of BG or TAD in a mouse model of SAD with a focus on the effects of PI3K/Akt, cGMP/protein kinase G (PKG) and Wnt/β-catenin signaling, as well as autophagy that all lead to initiation and perpetuation of neuroinflammation on AD hallmarks namely, Tau pathology, amyloidosis and associated cognitive deficits.
Section snippets
Animals
This study involved 8-weeks old male Swiss Albino mice (20–30 g). Animals were purchased from the breeding colony of the National Institute of Research (Giza, Egypt). Mice were kept under standardized laboratory conditions with free access to food and water. They were exposed to a 12-h light/dark cycle and controlled temperature (25 ± 5 °C). Before performing the experimental trials, the animals were allowed an adaptation period of 2 weeks. To minimize variability owing to circadian rhythm,
Effect of tadalafil or bergapten on the Morris water maze task
During the 4-day memory acquisition trial, the latency to find the hidden platform, MEL, progressively declined in all mice except for the STZ ones that showed a profound deterioration in their cognitive function as evidenced by the elevation of MEL by nearly 275% (F2.865 = 6.38), 304% (F5.14 = 16.08) and 402% (F 0.307 = 46.55) in the second, third and fourth training days, respectively as compared to the sham-control group (Fig. 1a). The prolonged latency for the STZ-induced SAD animals was
Discussion
This study provides new insights on the neuroprotective potential of the PDE5-I, TAD and the furanocoumarin, BG in AD-related cognitive, biochemical, and histological insults. Valuable assets of TAD or BG could be summarized as follows: (i) improvement of insulin signaling and neuronal survival by boosting pAkt, pGSK-3β, and mePP2A protein expression, as well as cGMP and PKG contents, while halting Tau hyperphosphorylation; (ii) refurbishment of the canonical Wnt/β-catenin signaling by
Conclusion
The present study accentuates the neuroprotective potential of the PDE5I, TAD, and the furanocoumarin, BG in an AD-like pathology as evidenced by the improved cognitive function and histological profile. The neuroprotective powers of TAD and BG could be ascribed to the modulation of the crosstalk among PI3K/Akt/GSK-3β, PP2A, mTOR/autophagy, cGMP/PKG, and Wnt/β-catenin pathways with diminution of neuroinflammation. This work provides a robust impetus into the likelihood of incorporating TAD or
Credit author statement
NS, SM, and MS generated the goal of research and performed the study design, methodology, creation of the experimental model and statistical analysis. JK & BB performed the isolation and identification of bergapten and contributed to writing the manuscript. NS, SM, and MS wrote the original draft of the manuscript. All authors read, revised and approved the final manuscript.
Declaration of Competing Interest
No conflict of interest is claimed by the authors. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Acknowledgment
The authors are grateful to Dr. Ahmed Othman (Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Egypt) for carrying out the histopathological examinations.
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