Someone posted a comment speculating over whether the recently announced interest in Paxalisib in treatments outside oncology might be for Alzheimer Disease. I found this paper:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8578535/The therapeutic possibility of the modulation of PI3K/Akt/mTOR in AD
Given the impact of the PI3K/Akt signaling axis in the progression of AD, new candidates with the ability to regulate this axis have joined the panoply of the drugs that are conventionally used for the treatment of this degenerative disease. Indeed, the activation or suppression of this axis widely depends on the type of the cells and also the stage of the disease. While suppression of the PI3K/mTOR axis could stimulate the autophagy system to eliminate the toxic proteins, the activation of PI3K could promote the survival of neural cells (Lipton and Sahin 2014). Therefore, it seems that both classes of drugs can be used to improve AD patients’ conditions, probably depending on the disease stage (Yu and Koh 2017). Thus far, it has been found that the therapeutic impact of several compounds on AD is mediated through modulating one component of the PI3K/Akt signaling axis. In the following part of this article, we are going to discuss some of the most important of these drugs, categorized as either chemicals or herbals.
mTOR modulation
Among different components of the PI3K/Akt/mTOR signaling axis, no component could have a straightforward effect on the pathogenesis of AD more than mTOR. The first chemical from the family of mTOR inhibitors used in the treatment of AD was rapamycin, which has brought advantages for patients through activating the autophagy system, delaying aging, and decreasing protein translation (Tsang 2007; Nazio 2013). Moreover, in response to rapamycin-mediated mTOR inhibition, Akt becomes activated in a compensatory manner and re-inhibits GSK-3β (Wang 2014b; Bhaskar and Hay 2007; Sarbassov 2005). Although rapamycin seems to be a valid drug for the treatment of AD, it has been suggested that the best time for the administration of this inhibitor is at the early stage of the disease when the activation of autophagy could instantly degrade toxic products (Majumder 2011). In this vein, a phase I study is recruiting AD patients at the early stage of the disease to evaluate the safety and tolerability of rapamycin (NCT04200911). However, given the emergence of several side effects, it was not long before that the second-generation of mTOR inhibitors found their way into the treatment strategies for AD. Notably, the suppressive impact of this class of mTOR inhibitors is not restricted only to mTORC1, as they could also inhibit the protein kinase activity of mTORC2 (Dowling, et al. 2010; Benjamin 2011). The dual PI3K/mTOR inhibitors such as PI103, NVPBEZ235, XL765, and SF1126 also bring advantages for AD patients by simultaneous suppression of mTORC1, mTORC2, and PI3K (Benjamin 2011; Zaytseva 2012). Bellozi et al. has reported that when transgenic AD mice were treated with NVPBEZ235 (5 mg/kg), the extent of social memory impairment was significantly reduced. Their results also reported the success of this inhibitor in suppression of microglial activation, which in turn reduced neuroinflammation in the brain tissue of the mice (Bellozi 2019). Another study conducted by Bellozi et al. suggested that NVPBEZ235 could significantly prevent the activation of microglia cells (Bellozi 2016).
Aside from chemicals, there are some natural compounds that have been reported to have beneficial impacts in AD through interacting with mTOR. Arctigenin, tripchlorolide, and β-asarone are, indeed, autophagy inhibitors, but their suppressive effects on the autophagy system are regulated through mTOR activation. Arctigenin could readily cross the blood–brain barrier and reduce the Aβ production rate in AD brains (Chang and Teng 2015; Deng 2016; Zeng 2015; Zhu 2013). Plants-derived alkaloids and flavonoids are also supposed to have a regulatory role on autophagy in neurons (Song et al. 2018; Umezawa 2018). The best examples of these compounds are found in Silybum marianum (Song 2017) and Dendrobium nobile Lindl (Li 2017); the extracts of which have improved Aβ clearance by stimulating the autophagy system.
