The role of Annexin A2 in Alzheimer's disease: From cellular functions to therapeutic potential.

According to the 2023 National Survey of Drug Use and Health survey, approximately 28.9 million individuals in the United States were affected by an alcohol use disorder (AUD). Although available pharmacotherapies for AUD exist, high rates of relapse persist due to various complex factors. Moreover, these treatments are effective only for certain populations, highlighting the need to develop effective therapeutic strategies and novel pharmacotherapies to reduce relapse. There is a critical need to identify the molecular signaling pathways involved in chronic alcohol use and relapse in order to identify therapeutic targets for novel pharmacotherapies. Drug relapse can be induced by a multitude of factors, including contextual cues and stress, which contribute to the formation and strengthening of drug-associated contextual memories. Furthermore, subjects with chronic alcohol use display enhanced memory for contexts associated with alcohol. The hippocampus is at the center of neurocircuitry involved in reward memory processing, including contextual information associated with reward memories. Specifically, accumulating evidence suggests that hippocampal subfield CA1 integrates dopamine reward signaling with contextual memories and regulates reward expectation and extinction. For example, exposure to alcohol can enhance future alcohol intake by altering contextual and cue hippocampal processes, highlighting the importance of acute changes (i.e., enhancement of cue, context, and reward processes) underlying learning processes following alcohol exposure. However, long-term exposure to alcohol can impair learning and memory by disrupting the hippocampal processes, and may contribute to generalized reward cues promoting relapse. While acute and chronic alcohol exposure may cause differential effects in the hippocampus, such as enhanced contextual alcohol reward memory compared with general memory impairments, it is clear that hippocampal circuits play a critical role in relapse. Therefore, improving our understanding of molecular factors in the hippocampus involved in chronic alcohol use may provide potential targets for the development of effective therapeutic approaches for AUD. Although pharmacotherapies are available for alcohol use disorder (AUD), effective treatments for context-induced relapse have not been identified. Furthermore, there is a lack of information regarding hippocampal alterations in chronic alcohol use in the primate hippocampus, limiting the development of novel therapeutic strategies. Current information from a small number of human studies is complicated by confounding factors inherent to human postmortem cohorts, such as comorbidities and medication exposure. We used a nonhuman primate model to examine the effects of chronic alcohol use on molecular pathways in the primate hippocampus, without the confounding factors typically present in human postmortem studies Fig. . Our bioinformatic approach also identified potential therapeutic targets that may reverse the gene expression signatures identified in subjects with chronic alcohol use.