7.5.2 – Implications of NAP for Alzheimer’s Disease and Beyond

Since NAP is a peptide fragment that is part of the neuroprotective protein ADNP, it is implicated in many neurodegenerative diseases that are characterized by lack of or decreased levels of this protein. NAP is therefore trialed for its effects on a range of diseases and disorders such as Alzheimer’s disease, fetal alcohol spectrum disorder as well as both intestinal and extraintestinal inflammation.

A 2017 study that looked at the effects of the pathogenic increase of Aβ1-42 in Alzheimer’s disease on neurological function of rats found that an increase in Aβ1-42 correlates with deficits in both memory and spatial learning in rats. These deficits were tested on a Morris water maze (MWM) test. An MWM test is a test in which rats are placed in a container full of liquid that has one raised surface above the liquid. The test subject is trained to reach that raised surface in order to be rescued. Once the subject learns that the raised surface is the escape spot, they would take less time to get there. The injection of Aβ1-42 in the rats’ hippocampus was, therefore, found to have increased the time it took the rats to find the escape spot. The intranasal application of Davunetide (NAP) was, however, found to reverse those findings thus making NAP a key drug to treat the memory deficits that patients suffering from AD have.

On a similar note, NAP was found to alleviate the neuronal deficits caused by alcohol in Fetal alcohol spectrum disorder (FASD). FASD is a neurodevelopmental disorder that occurs in children whose mothers drank alcohol during their pregnancy. It is characterized by deficits in growth, intellectual and developmental delays as well as facial abnormalities. The pathology of these disorders in the brain is mediated by an adhesion molecule known as L1 that is important in cell migration, axonal guidance as well as synapse formation. Alcohols like ethanol bind L1 as a result of a series of conformational changes on L1 that are mediated by actin cytoskeleton proteins like ankyrin-G. It is this interaction that NAP antagonizes. The binding of NAP inhibits the association of L1 with ankyrin-G thereby inducing a conformation of the protein that is unable to bind alcohol. These findings have the potential to allow mothers to use NAP while drinking during their pregnancies without the fear of potential neurodevelopmental problems for their fetus.

Outside the Central Nervous System, NAP was also found to have anti-inflammatory properties in both the intestines and the kidneys. In a 2017 study by Illana Gozes and her team, the intraperitoneal treatment of NAP given to mice with acute murine colitis was found to reduce pro-inflammatory mediators like IFN-γ, TNF and IL-6 while also increasing anti-inflammatory mediators like regulatory T lymphocytes. This was accompanied by a concurrent change in the gut microbiota of the mice resulting in an increase in healthy anti-inflammatory bacteria in the gut. In this study the NAP treatment also doubled bifidobacterial loads in the gut compared to the placebo treatment of NaCl. This makes NAP a therapeutic option for patients suffering from bowel inflammation.