It is interesting that Anthony Caggiano, M.D., Ph. D, the CMO and head of R&D at Cognition Therapeutics, a company investigating S2 receptor agonists for the treatment of neurodegenerative diseases, stated on Oct. 16, 2023, “The approval of monoclonal antibody therapies against amyloid beta protofibrils represents an important milestone in Alzheimer’s drug development, but industry experts agree that combination treatments will likely be required to achieve greater impact on the disease.” Dr. Timo Grimmer, an expert in neurodegenerative diseases and a member of Anavex’s SAB, has stated, “We all agree that combination therapy will be needed in the end.” One could argue that Anavex 2-73 is in itself a combination therapy, in light of the multitude of positive effects that it, or S1R agonists in general, have been shown to exert on the cell. This is not to say that it won’t be used in combination with other medications being developed by other companies. I believe it will.
In brief, these are some of the positive effects:
—it increases Nrf2, considered the master regulator of the cell’s antioxidant response
—it increases the expression of AMPK, considered a master cellular energy and re-dox sensing protein
—directly regulates amyloid beta production, an upstream effect
—regulates tau phosphorylation, another upstream effect
—improves neuron morphology by increasing dendrite spine formation, promoting growth cone formation, and potentiating
Nerve growth factor induced neurite sprouting and axon formation
—increases BDNF (brain derived neurotrophic factor), which promotes synaptic plasticity and neuronal survival
—promotes Ca ion exchange from the ER to the mitochondria(M) which increases ATP production from the electron transport chain
(neurons in AD are know to have deficient energy levels)
—by its antioxidant response, it decreases ROS production induced by A beta (ROS are known to damage many cellular elements such as 1) proteins, many of which are enzymes, causing misfolded or unfolded proteins, which causes ER and cellular stress; 2) nuclear DNA, causing toxic RNA, causing toxic proteins/enzymes, causing cellular and ER stress; 3) mitochondrial DNA, resulting in Mitochondrial dysfunction; 4) membranes, resulting in leaky membranes; 5) microglia, causing neuroinflammation by increasing cytokine production
—enhances MAM function, which plays an essential role in autophagy by promoting autophagosome-lysosome fusion and promoting TFEB nuclear translocation which causes transcription of the autophagy-related gene and lysosome biogenesis.
Anavex 2-73 specifically has been shown to increase autophagic flux by three-fold. The S1R is a surrogate biomarker of mitochondrial function. Note that S1R has been found classically at the MAM, but has also been found in mitochondria
Themselves as well as at the nuclear membrane, where it stabilizes nucleoporins , participating in transport of molecules between
The cytosol and the nucleus, such as TFEB mentioned above, many of which are chromatin remodeling components.
—S1R has been found to be able to bind with toxic RNA and clear it from the cytosol
—S1R affects the calcium concentration in the microglia, and inhibits microglia inflammatory response
—S1R is critical for the supportive function of astrocytes on neurons (it is the astrocytes that nourish the neurons)
—S1R is necessary for the formation of proper myelin sheaths and for the maturation of oligodendrocytes
—S1R increases glia-derived neurotrophic factor (GDNF) which enhances the integrity of the blood brain barrier
I think this is what Missling is referring to when he talks about the “complete housekeeping function” of Anavex 2-73.
