Skip to main content
. Author manuscript; available in PMC: 2023 Jan 25.
Published in final edited form as: Free Radic Biol Med. 2022 Oct 13;193(Pt 1):171–176. doi: 10.1016/j.freeradbiomed.2022.10.272

Figure 1. Concerted transnitrosylation reactions in the pathophysiology of synapse loss in Alzheimer’s disease (AD).

Figure 1.

Oligomerized amyloid-β peptide (Aβ), neuronal hyperexcitability, and aging-associated neuroinflammation trigger NO production via neuronal or inducible NO synthase (nNOS or iNOS), resulting in S-nitrosylated Uch-L1 (SNO-Uch-L1). Transnitrosylation from Uch-L1 to Cdk5 to Drp1 results in aberrant SNO-Drp1 formation, causing excessive stimulation of Drp1 and consequent mitochondrial fragmentation. The resulting bioenergetic failure contributes to synaptic damage underlying cognitive decline. NitroSynapsin is a novel, improved version of memantine with dual allosteric action of inhibiting excessive (mainly extrasynaptic) NMDAR activity, and therefore can abate, at least in part, damage to synapses by limiting excessive NMDAR activity and consequent RNS production via nNOS stimulation. The drug mechanism of action is (i) open-channel block of the NMDAR-associated ion channel when it is excessively open, mediated by the aminoadamantane moeity, and this facilitates (ii) targeted delivery of a nitroglycerin-like NOx moiety to S-nitrosylation sites(s) on the NMDAR that further inhibits excessive receptor activity [37, 38]. eNMDAR, extrasynaptic N-methyl-d-aspartate–type glutamate receptor; ROS, reactive oxygen species; RNS, reactive nitrogen species such as NO (adapted from [13]).